Results of a new study add to the evidence of an association between higher body mass index (BMI) and increased risk of cardiometabolic diseases such as hypertension, coronary heart disease, type 2 diabetes, according to a study published by JAMA Cardiology.
A connection between higher BMI and cardiometabolic disease risk usually arise from observational studies that are unable to fully account for confounding by shared risk factors. Mendelian randomization (a method of analysis using genetic information) is an approach that partially overcomes these limitations. Using mendelian randomization, Donald M. Lyall, Ph.D., of the University of Glasgow, Scotland, and colleagues conducted a study that included 119,859 participants in the UK Biobank (with medical, sociodemographic and genetic data) to examine the association between BMI and cardiometabolic diseases and traits.
Of the individuals in the study, 47 percent were men; average age was 57 years. The researchers found that higher BMI was associated with an increased risk of coronary heart disease, hypertension, and type 2 diabetes, as well as increased systolic and diastolic blood pressure.
These associations were independent of age, sex, alcohol intake, and smoking history.
The authors write that the results of this study has relevance for public health policies in many countries with increasing obesity levels. “Body mass index represents an important modifiable risk factor for ameliorating the risk of cardiometabolic disease in the general population.”
A limitation of the study was that the sample lacked data on a complete range of potential mediators, such as lipid traits and glucose levels.
A recent Danish study of children born to women with gestational diabetes, found that maternal daily consumption of artificially-sweetened beverages during pregnancy was associated with a higher body mass index score and increased risk of overweight/obesity at 7 years.
Artificial sweeteners are widely replacing caloric sweeteners, due to the health concern related to sugar-sweetened beverages (SSBs) within the general population. Artificially sweetened beverages have been considered as potential healthier alternatives, although this study suggests contrary. This study looks to investigate the long-term impact of ASBs consumption during pregnancy on offspring obesity risk in relation to offspring growth through age 7 years among children born to women with gestational diabetes .
In particular, children born to women with gestational diabetes –the most common pregnancy complication affecting approximately 16% of pregnancies worldwide–represent a high-risk phenotype, which may serve as a unique model to study the early origins of obesity. Further evidence has linked nutritional biological disruptions during pregnancy to fetal development and obesity risk in later life. Thus, the authors argue it is important to identify modifiable dietary factors that may prevent offspring obesity and maternal complications.
The study investigated 918 mother and child pairs from the Danish National Birth Cohort. Enrolled participants completed four telephone interviews at gestational weeks 12 and 30, and 6 and 18 months postpartum, which collected data on sociodemographic, perinatal, and clinical factors. In addition, maternal dietary intake was assessed by a food questionnaire during pregnancy. Offspring body mass index scores and overweight/obesity status were calculated using weight and length/height at birth, 5 and 12 months, and 7 years. When the children were 7 years old, a follow-up questionnaire about the child’s health and development was delivered to the parents.
Results showed that approximately half (45.4%) of women reported consuming artificially sweetened beverages during pregnancy. Whereas 68.7% reported consuming SSBs, artificially sweetened beverage consumption–compared to never consuming artificially sweetened beverages–by pregnant women with gestational diabetes was associated with a 1.57 increased risk of being overweight for gestational age babies and a 1.93-fold increase in overweight/obesity risk at 7 years after adjustment for major maternal and offspring risk factors.
Associations were more pronounced in male than female offspring. Substituting SSBs with artificially sweetened beverages was associated with an increased risk of offspring overweight/obesity at 7 years whereas substitution of artificially sweetened beverage with water was associated with a 17% reduced risk. The findings illustrated a positive association between uterus exposure to artificially sweetened beverages and birth size and risk of overweight/obesity at 7 years.
Overconsumption of a Western diet high in fats and refined sugars has contributed to a global increase in obesity and Type 2 diabetes. Obese and diabetic premenopausal women are more at risk of developing heart disease — even more than men of similar age and with similar health issues. A study by researchers at the University of Missouri School of Medicine found that the diabetes medication linagliptin can protect against stiffening of the left ventricle of the heart in overweight female mice. The finding may have implications for management of cardiovascular diseases in humans.
“In previous studies, we showed that young, female mice consuming a Western diet, high in fat, sucrose and high fructose corn syrup, not only gained weight, but also exhibited vascular stiffening consistent with obese premenopausal women,” said Vincent DeMarco, Ph.D., a research associate professor of endocrinology at the MU School of Medicine and the lead author of the study. “Our current study sought to understand if linagliptin prevents cardiac stiffening caused by eating a Western-style diet.”
Linagliptin is a medication prescribed to lower blood glucose in patients with Type 2 diabetes. The medication works by blocking the enzyme dipeptidyl peptidase-4, or DPP-4. Previous studies have shown that DPP-4 inhibitors offer protection against vascular inflammation and oxidative stress — conditions associated with cardiovascular stiffening.
DeMarco’s team studied 34 female mice that were fed either a normal diet or a simulated Western diet for four months. Another group of mice were fed a Western diet containing a low dose of linagliptin. The team used an ultrasound system, similar to that used in humans, to evaluate the function of the left ventricle of the heart.
“A heartbeat actually is a two-part pumping action that takes less than a second in healthy humans,” DeMarco said. “The first part, known as diastole, involves relaxation of the left ventricle while it fills with oxygenated blood from the lungs. After the left ventricle fills with blood, it then contracts and pushes blood into the aorta. This part of the cardiac cycle is referred to as systole. If the left ventricle becomes stiffer it will not be able to relax normally, and diastole will be impaired. This form of heart disease is known as diastolic dysfunction, which is a risk factor for a more serious heart condition known as diastolic heart failure.”
The mice fed the Western diet alone gained weight, exhibited increased heart weight and developed diastolic dysfunction. However, the mice fed the Western diet along with linagliptin did not develop diastolic dysfunction. They also exhibited less oxidative stress and inflammation in their hearts compared to the mice fed the Western diet alone.
“Oxidative stress and inflammation are two factors that can promote excess accumulation of collagen, also known as fibrosis, in the walls of the left ventricle,” DeMarco said. “In our study, we found that Western diet-fed mice had increased fibrosis in the left ventricle that was prevented by linagliptin.”
The team also found that linagliptin suppressed not only DPP-4 activity, but also TRAF3IP2 production. TRAF3IP2 is a protein responsible for initiating tissue oxidative stress, inflammation and fibrosis in the heart.
“This was a major novel finding of our study,” DeMarco said. “However, further research is required to determine exactly how linagliptin affects the function of this important protein.”
DeMarco also cautioned that linagliptin, like other DPP-4 inhibitors, can be expensive without insurance coverage.
“Based on the results of this research and our previous studies, it is tempting to speculate that linagliptin could reduce the risk of cardiovascular complications associated with obesity and Type 2 diabetes,” DeMarco said. “However, ongoing clinical trials will help determine what, if any, cardio-protective role linagliptin could play in the management of obesity-related heart disease.”
More than 387 million people are living with diabetes worldwide. This number is expected to grow to 592 million by 2035. Effective daily blood glucose monitoring is a huge factor in the health and wellbeing of diabetics. A new mobile health app and all-in-one blood glucose monitor system from DarioHealth Corp. (DRIO) can improve monitoring and outcomes for diabetics.
The Dario™ Smart Diabetes Management Solution is a platform for diabetes management that combines an all-in-one blood glucose meter, native smart phone app (iOS & Android), website portal and a wide variety of treatment tools to support more proactive and better informed decisions by users living with diabetes, their doctors and healthcare systems.
Users in the U.S. can take advantage of 3rd party insurance coverage to have the DarioHealth products reimbursed by insurance. DarioHealth signed strategic alliance agreements with partners across the U.S. who will be able to verify insurance coverage benefits, and if approved, will supply and bill the customer’s insurance for their Dario™ Blood Glucose Monitoring System and test strip supplies. During DarioHealth’s pilot phase of this insurance coverage option, partners were able to verify benefits for customers covered by Aetna and various Blue Cross Blue Shield plans.
DarioHealth plans to expand its reach and add additional providers and insurance coverage options for those who want to utilize the insurance benefits available to them.
Mobile health applications can significantly improve patient outcomes. Healthcare is one of the fastest growing categories in the app market. At present, 45,000 app publishers are responsible for some 165,000 mHealth apps available on the market. Mobile health app adoption has doubled in 2 years, from 2013 to 2015.
Namodenoson, a Phase II drug developed by Can-Fite BioPharma Ltd. (NYSE MKT: CANF), has shown in newly published data that it prevents liver (hepatic) fibrosis progression in preclinical studies.
“These latest study results add to the growing body of data that demonstrate Namodenoson’s potential efficacy in combating non-alcoholic fatty liver disease (NAFLD), the precursor to non-alcoholic steatohepatitis (NASH), indications for which there is currently no FDA approved drug. We are advancing Namodenoson into a Phase II trial in NAFLD and expect to commence patient enrollment in the coming months through leading medical institutions in Israel,” stated Can-Fite CEO Dr. Pnina Fishman.
NAFLD is characterized by excess fat accumulation in the form of triglycerides (steatosis) in the liver. According to a recent study published in Hepatology, an estimated 25% of the population in the U.S. has NAFLD, with a higher prevalence in people with type II diabetes. Incidence is increasing based on rising obesity rates. NAFLD includes a range of liver diseases, with NASH being the more advanced form, manifesting as hepatic injury and inflammation. According to the NIH, the incidence of NASH in the U.S. is believed to affect 2-5% of the population. The spectrum of NAFLDs resembles alcoholic liver disease; however, they occur in people who drink little or no alcohol. If untreated, NASH can lead to cirrhosis and liver cancer.
By 2025, the addressable pharmaceutical market for NASH is estimated to reach $35-40 billion.
Liver fibrosis is the excessive accumulation of scar tissue resulting from ongoing inflammation. It can result in diminished blood flow throughout the liver and is associated with NAFLD.
Recent preclinical studies in a mouse model of liver fibrosis demonstrated the anti-fibrotic effects of Namodenoson. The Namodenoson treated group exhibited normal liver under macroscopic view, no accumulation of fluid (ascites), a low fibrosis profile, and lower serum levels of transaminases as compared to the control group. In addition, liver protein extracts and mRNA for the alpha smooth muscle actin showed a significant anti-fibrotic effect in the Namodenoson treated group as compared to the control group.
These studies were conducted under the supervision of Prof. Rifaat Safadi M.D., a Key Opinion Leader in the field of liver diseases, and Director of Liver Unit, Institute of Gastroenterology and Liver Diseases, Hadassah University Hospital, Ein Kerem.
Prof. Safadi commented, “Lowering liver fat content and fibrosis are the main unmet needs in NASH. Today there is a huge market need for drugs that fight the worldwide NASH epidemic.”
“Namodenoson is uniquely compelling for its potential to treat NAFLD and NASH because its safety profile has already been de-risked, increasing the likelihood it can advance through late stage trials and into clinical use for this large and unmet need,” Dr. Safadi added. “In general, there is significant development risk for new potential drugs in development due to safety risks including drug induced liver injury (DILI), drug-to-drug interactions (DDI), and metabolites in safety testing (MIST). Namodenoson, however, has demonstrated a good safety profile and is low or negative for DILI, DDI and MIST.”
“In addition, Namodenoson recognizes the difference between diseased and normal cells, and targets only the diseased cells through the specific A3 adenosine receptor. This precision targeting is designed to lead to higher efficacy and safety by leaving healthy cells unaffected. We are all looking for drugs with this profile to treat NASH,” concluded Dr. Safari.
Can-Fite plans to commence patient recruitment for its Phase II trial of Namodenoson in NASH/NAFLD in the second quarter of 2017.
Researchers at Bascom Palmer Eye Institute, part of the University of Miami Miller School of Medicine, have identified a new molecule that induces the formation of abnormal blood vessels in the eyes of diabetic mice. The study, “Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy,” which will be published March 22 in The Journal of Experimental Medicine, suggests that inhibiting this molecule may prevent similarly aberrant blood vessels from damaging the vision of not only diabetics, but also premature infants.
Changes in the vasculature of diabetes patients can cause long-term complications such as diabetic retinopathy, which affects around 93 million people worldwide. Many of these patients suffer a dramatic loss of vision as the blood vessels supplying the retina become leaky and new, abnormal blood vessels are formed to replace them. A molecule called vascular endothelial growth factor (VEGF) regulates blood vessel growth and leakiness, and two VEGF inhibitors, ranibizumab (Lucentis) and aflibercept (Eylea), have been approved to treat retinal vascular leakage, though they are only successful in about a third of patients.
The growth of abnormal new blood vessels also causes retinopathy of prematurity (ROP), the most common cause of vision loss in children that affects up to 16,000 premature infants per year in the US. VEGF inhibitors are not approved for use in these patients because VEGF is crucial for vascular development in newborn children.
Study lead-author Wei Li, Ph.D., research associate professor, and his colleagues at Bascom Palmer developed a technique called “comparative ligandomics” to identify additional molecules that regulate the behavior of blood vessels in diabetic mice. The approach allows the researchers to compare the signaling molecules that selectively bind to the surface of retinal blood vessel cells in diabetic but not healthy animals.
“It is estimated that between one third and one half of all marketed drugs act by binding to cell surface signaling molecules or their receptors,” says Li. “Our ligandomics approach can be applied to any type of cell or disease to efficiently identify signaling molecules with pathogenic roles and therapeutic potential.”
Using this technique, Li and colleagues discovered that a protein called secretogranin III (Scg3) efficiently binds to the surface of retinal blood vessel cells in diabetic, but not healthy, mice. Though Scg3 promotes the secretion of hormones and other signaling factors, it wasn’t thought to have a signaling function itself. Nevertheless, the researchers found that Scg3 increased vascular leakage, and, when administered to mice, it stimulated blood vessel growth in diabetic, but not healthy, animals.
VEGF, in contrast, stimulates blood vessel growth in both diabetic and healthy mice. Li and colleagues think that Scg3 binds to a distinct cell surface receptor that is specifically up-regulated in diabetes.
Treating diabetic mice with Scg3-neutralizing antibodies dramatically reduced the leakiness of their retinal blood vessels. Moreover, the antibodies significantly inhibited the growth of new blood vessels in mice with oxygen-induced retinopathy, a well-established animal model of human ROP.
Though the researchers still need to confirm the role of Scg3 in humans, inhibiting this protein could be an effective treatment for both diabetic retinopathy and ROP, especially as it appears to have no role in normal vascular development. “Scg3 inhibitors may offer advantages such as disease selectivity, high efficacy, and minimal side effects,” Li says. “Because they target a distinct signaling pathway, anti-Scg3 therapies could be used in combination with, or as an alternative to, VEGF inhibitors.”
Study reveals single cell type and surface molecule sufficient to cause common complication
Specific cells in the retina trigger inflammation and vision impairment associated with diabetes, according to new research out of Case Western Reserve University School of Medicine. The findings unexpectedly implicate Müller cells—which provide structural support in the retina—as key drivers of the process. Researchers now have a therapeutic target in hand and understand initial steps of diabetic retinopathy, one of the most common and debilitating side effects of diabetes.
Carlos Subauste, MD, Associate Professor of Medicine and Pathology and Timothy Kern, PhD, Professor of Medicine, Ophthalmology and Pharmacology at Case Western Reserve University School of Medicine led the research, recently published in Diabetes. Said Subauste, “Our studies uncovered a novel mechanism that explains the development of experimental diabetic retinopathy. Diabetic retinopathy is the leading cause of visual impairment in working age adults in the western world.”
In the study, Subauste and his team zeroed in on a receptor protein that sits on the surface of Müller cells. They discovered the receptor, CD40, sends signals to nearby cells called microglia and macrophages to initiate harmful inflammation in the retina. But, CD40 is a regular on the surfaces of many cells, so Subauste and his team had to devise a clever strategy to determine which cells initiate the harmful chain of events.
“From studies done with Dr. Kern, we knew mice with no CD40 are protected from diabetic retinopathy,” said Subauste. “We created transgenic mice that only express CD40 on Müller cells to further examine the role of the receptor.” The researchers discovered that mice with the receptor limited to Müller cells still developed retinopathy. A closer look revealed that CD40 also elicits pro-inflammatory molecules from bystander microglia and macrophages. The researchers found that CD40 makes Müller cells secrete a small energy molecule called ATP. In turn, ATP engages a specific receptor on the surface of microglia and macrophages triggering inflammatory responses in these cells.
The researchers had found their culprit. Their study provides direct evidence that a single receptor on the surface of Müller cells is sufficient to cause harmful inflammation that leads to experimental diabetic retinopathy.
Said Subauste, “Our study identifies CD40 as a therapeutic target against diabetic retinopathy.” The prevalence of the receptor throughout the body suggests the findings may also be applicable to inflammatory bowel disease, atherosclerosis, or lupus.
“Add-back of CD40 represents an elegant means of testing the hypothesis,” said a commentary in the journal featuring the study, calling the findings “unprecedented.”
Diabetic retinopathy is a major complication of diabetes that impairs the ability of the retina to sense light. For years, scientists have implicated inflammation as a primary driver of the complication, but it has been difficult to tease apart the many cells and signal molecules involved.
Said Subauste, “The choice of Müller cells was not obvious since it would have been logical to predict that CD40 expressed on microglia, macrophages, or endothelial cells, would have been the major driver of inflammation in the retina.” Instead, the researchers discovered CD40 on Müller cells activates these cell types, which are often implicated in inflammation.
Subauste teamed up not only with Timothy Kern, PhD but also with George Dubyak, PhD, Professor of Physiology and Pharmacology at Case Western Reserve University School of Medicine for the groundbreaking study. Subauste and Kern are now combining the mouse models with pharmacologic interventions identified by Subauste that block inflammatory processes induced by CD40, to ultimately prevent diabetic retinopathy.
Researchers in China have discovered that a metabolic enzyme called AKR1B1 drives an aggressive type of breast cancer. The study, “AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program,” which has been published in The Journal of Experimental Medicine, suggests that an inhibitor of this enzyme currently used to treat diabetes patients could be an effective therapy for this frequently deadly form of cancer.
Around 15–20% of breast cancers are classified as “basal-like.” This form of the disease, which generally falls into the triple-negative breast cancer subtype, is particularly aggressive, with early recurrence after treatment and a tendency to quickly spread, or metastasize, to the brain and lungs. There are currently no effective targeted therapies to this form of breast cancer, which is therefore often fatal.
Crucial to basal-like breast cancer’s aggressiveness is a process called epithelial-mesenchymal transition (EMT), in which the cancer cells become more motile and acquire stem cell-like properties that allow them to resist treatment and initiate tumor growth in other tissues.
Chenfang Dong and colleagues at the Zhejiang University School of Medicine in Hangzhou, China, found that the levels of a metabolic enzyme called AKR1B1 were significantly elevated in basal-like and triple-negative breast cancers and that this was associated with increased rates of metastasis and shorter survival times.
The researchers discovered that AKR1B1 expression was induced by Twist2, a cellular transcription factor known to play a central role in EMT. AKR1B1, in turn, elevated Twist2 levels by producing a lipid called prostaglandin F2 that activates the NF-B signaling pathway. This “feedback loop” was crucial for basal-like cancer cells to undergo EMT; reducing AKR1B1 levels impaired the cells’ ability to migrate and give rise to cancer stem cells.
Knocking down AKR1B1 also inhibited the growth and metastasis of tumors formed by human basal-like breast cancer cells injected into mice. “Our data clearly suggests that AKR1B1 overexpression represents an oncogenic event that is responsible for the aggressive behaviors of basal-like breast cancer cells,” Dong explains.
Moreover, epalrestat, a drug that inhibits AKR1B1 and is approved in Japan to treat peripheral neuropathies associated with diabetes, was similarly able to block the growth and metastasis of human basal-like breast cancer cells. “Since epalrestat is already on the market and has no major adverse side effects, our study provides a proof of principle that it could become a valuable targeted drug for the clinical treatment of basal-like breast cancer,” Dong says.
by Richard (Rick) Mills, editor of aheadoftheherd.com
As a general rule, the most successful man in life is the man who has the best information
The promise of regenerative medicine is to treat disease and injury by replacing, regenerating or rejuvenating various parts of the human body that have been damaged by chronic disease, traumatic injury, heart attack, stroke, or aging. Treatments include both in vivo (studies and trials performed inside the living body) and in vitro (treatments applied to the body through implantation of a therapy studied inside the laboratory) procedures.
After many years of research the potential for regenerative medicine to redress the increasing prevalence of degenerative chronic diseases and acute injuries is beginning to receive huge scientific and public interest.
And no wonder! Look at some of the things we can already do…
Spina bifida suffers can now receive a bladder grown from their own cells.
Researchers have bioengineered a human liver that can be implanted into mice.
Heart disease affects the valves of the heart causing them to fail, we’ve already successfully grown heart valves from human cells.
Researchers have regenerated kidney tissue that is able to clear metabiolites, reabsorb nutrients and produce urine both in vitro and in vivo in rats.
Surgeons can now implant a tiny telescope within the eye helping restore some of the vision lost to end-stage age-related macular degeneration (AMD).
A material developed from the small intestines of pigs – small intestinal submucosa (SIS) – is used for everything from reconstructing ligaments, closing hard-to-heal wounds and treating incontinence.
Less complex organs such as the bladder and the trachea have been constructed from a patient’s cells and scaffolds and successfully transplanted.
Tissue-engineered vascular grafts for heart bypass surgery and cardiovascular disease treatment are at the pre-clinical trial stage.
New approaches to revitalizing worn-out body parts include removing all of the cells (decellularization) from an organ, and infusing new cells (recellularization) to integrate into the existing matrix and restore full functionality.
“The first crop of simple stem cell therapies for regenerative medicine has reached widespread availability in the developed world. “Simple,” because these therapies are on the level of transfusions. In most cases stem cells are obtained from the patient, then grown in a cell culture and the greatly expanded number of cells injected back into the body. New medicine doesn’t get much simpler than that in this day and age. This is merely the start of a revolution in medicine, however, one will grow to become as large and as influential on health as the advent of blood transfusion or the control of common infectious diseases…Research continues, with a tone of excitement coming from the scientific community. They know they are onto something big.” Fightaging.org, Stem Cells, Regenerative Medicine, and Tissue Engineering
Some ongoing studies:
Diabetics treated with stem cell therapies that grow new insulin making cells.
Researchers are developing strategies to deliver proteins directly to the brain of stroke patients to stimulate stem cells and promote tissue repair.
Halting the progression of ALS, amyotrophic lateral sclerosis (also known as Motor Neuron disease and Lou Gehrig’s disease) and multiple sclerosis (MS).
Regrowing muscles in soldiers who were wounded in an explosion.
Restoration of Factor VIII in hemophiliacs.
The potential benefits of genetically enhanced stem cells in healing severe heart attacks.
It has to be pretty clear by now that regenerative medicine, although still in the early stages, is in the process of changing the practice of medicine.
These therapies will not only change healthcare, but will also lead to commercial success for the company and success in the market for investors.
One regenerative medicine company that’s currently off investors radar screens is Sernova Corp. (TSX-V: SVA, OTCQB: SEOVF, FSE: PSH).
However, with all Sernova has going on for it, the academic partnerships and R&D alliances, the company will begin to attract serious market attention, and possibly big pharma attention, in 2017.
Sernova Corp. is a clinical stage regenerative medicine company developing their Cell Pouch System™ for the treatment of chronic debilitating metabolic diseases such as diabetes, blood disorders including hemophilia and other diseases treated through replacement of proteins or hormones missing or in short supply within the body.
Sernova Corp. has developed the subcutaneous Cell Pouch™ and has specifically designed it to overcome the issues with previous implanted devices for cell transplantation.
Sernova’s implantable prevascularized macro-encapsulated Cell Pouch™ is a versatile and scalable, first-in-class medical device made entirely of FDA approved materials. The Cell Pouch System™ provides a natural “organ-like” environment rich in tissue matrix and micro-vessels. This is the ideal environment for therapeutic cells to thrive which then release proteins and/or hormones as required.
Sernova’s extensive preclinical safety and efficacy studies have shown this device to be both safe and effective, while being sparing of islets, supporting its design and function. The Cell Pouch™ being thin and typically smaller than a business card, fits easily under the skin with virtually no visibility.
Sernova Corp.’s Cell Pouch™, using human donor islet cells to produce insulin, should begin formal U.S. Food and Drug Administration (FDA) directed clinical testing in Type I/II diabetes early in 2017.
Phase I clinical human testing with porcine-derived islets and formal human studies using stem cell-derived islet cells will follow.
Sernova has entered into partnerships with the University of Toronto (a stem cell-derived diabetes technology licensing/alliance), Harvard University and the University of Chicago.
Sernova’s Cell Pouch™ potential is not limited to just islet cell transplantation in diabetes. Sernova has an R&D collaboration ongoing to develop cell therapies for treating hemophilia A (already funded from the European Commission’s Horizon 2020 program), and a separate alliance with the University of British Columbia focused on thyroid disorders.
Regenerative medicine could potentially provide lasting solutions to some of the world’s leading chronic diseases. That will massively impact the medical industry in coming years. The regenerative medicine market, still in its infancy, offers a genuine opportunity for investors.
Big pharmaceutical companies are beginning to show increased interest by making various acquisitions and engaging in partnership programs with startup research companies.
“The rapid aging of the global population and the increasing prevalence of obesity is leading to a significant and growing rate of inflammatory and degenerative diseases of all types. These demographically driven changes are generating significant interest from large, multi-national pharmaceutical companies now targeting small biotechnology start-ups engaged in developing diagnostics and treatments for these degenerative diseases.”
By the year 2020, baby boomers – people aged 65 and up – will outnumber children under age 5 globally. Also, by the year 2020, the Department of Health and Human Services predicts the market for regenerative medicine will reach $300 billion.
Companies, such as Sernova Corp., are the leaders in preclinical research and many, like SVA is, are entering Phase I/II clinical trials. These company’s become significant targets once they successfully get their products to a stage warranting the attention of the big players.
The magnitude of the present opportunity for an investment into Sernova is equaled only by the enormous potential return once one of SVA’s therapies reaches the market, or more likely draws the attention of big pharma.
“A new branch of medicine will develop that attempts to change the course of chronic disease and in many instances will regenerate tired and failing organ systems.” Leland Kaiser, recognized futurist and acknowledged authority on the changing American healthcare system
Harnessing the power of stem cells to repair or replace cells, tissues or organs that are damaged by trauma or disease means we are entering an era where treatments for some of the world’s most devastating diseases are developed.
Lab manufactured therapeutic cells hosted in the human body, in SVA’s prevascularized Cell Pouch System™ monitoring, regulating, manufacturing and secreting the necessary hormones, factors and proteins to control diabetes and hemophilia would be a major accomplishment.
The transformational potential of stem cells, placed within Sernova’s prevascularized Cell Pouch(TM) could:
Treat diseases in a much better way than traditional drugs/treatments
Significantly improve the quality of patient’s lives
Offer a faster, more complete recovery with significantly fewer side effects or risk of complications
Reduce the cost of healthcare
Prevent premature mortality
Bring significant indirect economic benefits not only to patients but society as a whole
It would be hard to argue against my position that Sernova Corp., and the regenerative medicine sector as a whole, will have taken a massive step forward if upcoming human Phase I/II clinical trials are successful.
Sernova is today a relatively unknown pure regenerative medicine play that has partnered their Cell Pouch™ with a network of academic cell therapy research and development partners.
For these two reasons Sernova, and a well timed investment in the regenerative medicine space, best be on your radar screen. Is it?
If not, it should be.
Richard (Rick) Mills
Richard lives with his family on a 160 acre ranch in northern British Columbia. He invests in the resource and biotechnology/pharmaceutical sectors and is the owner of aheadoftheherd.com.
Legal Notice / Disclaimer
This document is not and should not be construed as an offer to sell or the solicitation of an offer to purchase or subscribe for any investment.
Richard Mills has based this document on information obtained from sources he believes to be reliable but which has not been independently verified.
Richard Mills makes no guarantee, representation or warranty and accepts no responsibility or liability as to its accuracy or completeness. Expressions of opinion are those of Richard Mills only and are subject to change without notice.
Richard Mills assumes no warranty, liability or guarantee for the current relevance, correctness or completeness of any information provided within this Report and will not be held liable for the consequence of reliance upon any opinion or statement contained herein or any omission.
Furthermore, I, Richard Mills, assume no liability for any direct or indirect loss or damage or, in particular, for lost profit, which you may incur as a result of the use and existence of the information provided within this Report.
Richard owns shares of Sernova Corp. (TSX-V: SVA, OTCQB: SEOVF, FSE: PSH). Sernova is an advertiser on Richard’s site – aheadoftheherd.com.
According to the World Health Organization, 422 million adults across the globe have diabetes. In fact, the number of adults with the disease continues to grow each year.
To help the growing patient population, researchers at the University of Michigan are going down to the molecular level. Here, they’re trying to determine what makes cells in the diabetic pancreas less efficient in generating insulin molecules.
Diabetes occurs when the body’s pancreas does not produce enough insulin to keep blood sugar levels under control.
“Ten years ago, we found that when insulin is being made in the pancreatic beta cells, a certain subfraction of new synthesized insulin molecules, called proinsulin, cannot fold properly,” says Ming Liu, Ph.D., research associate professor of internal medicine at U-M and co-investigator on a new study on the topic.
“This problem is known as proinsulin misfolding, and several different groups around the world have now come up with similar observations. We also found that in animals in which production of misfolded proinsulin molecules reaches 30 percent of total proinsulin, that is enough for these animals to develop diabetes from pancreatic beta cell failure.”
A four-member team of U-M faculty are currently zeroing in on misfolded proinsulin.
“When you are born, you receive two copies of the gene encoding proinsulin, one from your mom and one from your dad,” says Billy Tsai, Ph.D., co-investigator and professor of cell and developmental biology at U-M. “There is a special kind of diabetes, called Mutant Ins-gene Induced Diabetes of Youth (MIDY), in which the patients with diabetes have a mutation in one of the copies so that as much as half of all of their proinsulin may be misfolded.”
Tsai explains that in the pancreatic beta cell, proinsulin first is targeted, or delivered, to the endoplasmic reticulum (ER) compartment, in order to begin the process of making insulin. When proteins are made in the ER, if things go right, they acquire their natural folded three-dimensional shape that is needed in order to function as they should.
If they don’t acquire and retain that proper shape, then the cell recognizes them as being defective protein molecules and works to destroy them so that they don’t wreak havoc within the cell.
“In the MIDY disease, having that one mutated gene making proinsulin is bad news,” Tsai says. “The cell has to figure out a way to recognize the bad protein molecules that come from the mutant gene and destroy them. And if it doesn’t, it turns out that misfolded proinsulin can have a “dominant-interfering” effect on the normal bystander proinsulin molecules that are made from the other, good gene.”
He adds that the normal proinsulin would ordinarily be made into insulin and that would help to lower blood sugar. But, when the misfolded proinsulin physically attaches itself to the normal bystander proinsulin, that blocks the ability of beta cells to make the normal proinsulin into insulin.
Liu and Tsai are joined in the study by U-M colleagues Peter Arvan, M.D., Ph.D., professor and chief of the Division of Metabolism, Endocrinology & Diabetes, and Ling Qi, Ph.D., professor of molecular and integrative physiology.
The team explains that the pancreatic cells have a way of rectifying the protein misfolding problems. The major way is by recognizing misfolded or damaged proteins and ejecting them from the ER to the cell’s proteosome, a major cellular garbage disposal that has the responsibility of chopping up proteins targeted for destruction. That process is called Endoplasmic Reticulum Associated Degradation (ERAD).
The idea is that if misfolded proinsulin is chopped up and degraded, then the remaining normal proinsulin can move through the beta cell and be successfully converted into biologically active insulin, to lower blood sugar.
The team is now researching if there is a way to stimulate the degradative pathway in order to get rid of more of the mutant protein.
“We think we can rectify this diabetic disease by manipulating the ERAD pathway so we can restore normal insulin secretion,” says Tsai.
“We’re trying to show proof of principle that if we manipulate the cells to have increased ability to degrade misfolded proinsulin, we can increase the amount of normal insulin that can be made and secreted. The hope is this would then help in the development of drugs that would stimulate ERAD to generate the same beneficial effect.”
The team explains this type of research has not been reported before in the diabetes field.
“There have been extensive studies on proteins undergoing ERAD,” says Qi. “Researchers know that protein misfolding is important for certain diseases, but we’re now focusing in on diabetes.”
Arvan agrees, “To understand protein misfolding diseases, we have to know more about protein folding. This is an exciting step in the field of diabetes research.”
The team has just received a four-year, multi-investigator grant from the National Institutes of Health, from which important new answers are expected.
Immunotherapies have shown great promise to treat a wide range of diseases including auto-immune disease and NASH. However, they are typically administered through IV instead of orally because if taken orally, they would be degraded and inactivated by the harsh conditions in the gastrointestinal tract. New data from preclinical studies conducted by Prof. Kevan Herold of Yale University and Prof. Howard Weiner of Harvard University show that Foralumab, a drug from London-based Tiziana Life Sciences, has shown consistent efficacy via oral administration. Oral efficacy with Foralumab is a potential game-changer for the treatment of autoimmune diseases and NASH.
Foralumab is a long half-life therapeutic mAb candidate with high affinity and potency for CD3 epsilon. It is the only fully human engineered anti CD3 monoclonal antibody (mAb) in clinical development. The unique oral technology stimulates the natural gut immune system and potentially provides a therapeutic effect in inflammatory and autoimmune diseases with virtually no toxicity.
According to Prof. Kevan Herold, a member of Tiziana’s Scientific Advisory Board at Yale University, “This study demonstrates that oral administration works consistently in our pre-clinical models with human immune cells. This suggests that oral CD3-specific mAb has the potential for treating NASH, diabetes, and other autoimmune diseases in humans – an entirely novel approach for the treatment of currently unmet needs.”
Further animal studies conducted in a member of Tiziana’s Scientific Advisory Board, Prof. Howard Weiner’s laboratory at Harvard University, supported the potential of oral treatment with Foralumab for autoimmune and inflammatory diseases. Prof. Weiner stated, “Our data suggest that oral treatment with anti-CD3 mAb induces an anti-inflammatory response through induction of regulatory T cells (Tregs). This proof of concept of foralumab in humanized mice demonstrates that this approach could be used successfully in humans as well.”
Foralumab has applications in chronic inflammatory and autoimmune diseases with high unmet medical needs such as ulcerative colitis, inflammatory bowel diseases, multiple sclerosis, lupus, as well as in non-alcoholic steatohepatitis (NASH) and type 1 diabetes.
Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, published in EMBO Molecular Medicine, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.
AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.
While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.
“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.
Scientists at Columbia University Medical Center (CUMC) have identified a factor in liver cells that is responsible for turning a relatively benign liver condition, present in 30 percent of U.S. adults, into a serious disease that can lead to liver failure.
The study was published online today in Cell Metabolism.
With the rise of obesity in the U.S., the incidence of nonalcoholic fatty liver disease (NAFLD)—in which excess fat fills the liver—has risen to epidemic levels. The extra liver fat is generally benign, but in one in five people, NAFLD evolves into a more serious condition, nonalcoholic steatohepatitis (NASH).
In NASH, the liver becomes inflamed and criss-crossed by fibrous scar tissue, and liver cells start dying. Patients with NASH are at risk of liver failure and liver cancer, but there are no drugs on the market that can slow or stop the disease.
Because the amount of fibrosis in the liver is associated with a greater risk of death from NASH, Xiaobo Wang, PhD, associate research scientist in the Department of Medicine at CUMC working in the lab of Ira Tabas, MD, PhD, looked for ways to stop fibrosis in a mouse model of NASH.
He found that in liver cells, TAZ, a previously unknown factor in NASH, plays a critical role in initiating fibrosis, and that fibrosis stops in mice with NASH when TAZ is inactivated in liver cells. With TAZ shut down, existing fibers in the liver also dissolved, essentially reversing the disease. Two other critical features of NASH, inflammation and cell death, were also reduced when TAZ was turned off. Fat accumulation in the liver was unaffected.
Based on their examination of liver biopsies from NAFLD and NASH patients, Drs. Wang and Tabas believe that TAZ works in the same way in people.
“We think that by stopping fibrosis through TAZ and its partners, we may be able to prevent the serious consequences of NASH, including liver failure and liver cancer,” said Ira Tabas, Richard J. Stock Professor and vice-chair of research in the Department of Medicine and professor of pathology & cell biology (in physiology and cellular biophysics) at CUMC.
University of Alabama at Birmingham researchers are exploring ways to wrap pig tissue with a protective coating to ultimately fight diabetes in humans. The nano-thin bilayers of protective material are meant to deter or prevent immune rejection.
The ultimate goal: transplant insulin-producing cell-clusters from pigs into humans to treat Type 1 diabetes.
In preclinical work begun this year, these stealth insulin-producers — pancreatic islets from pigs or mice coated with thin bilayers of biomimetic material — are being tested in vivo in a mouse model of diabetes, say UAB investigators Hubert Tse, Ph.D., and Eugenia Kharlampieva, Ph.D. Tse is an immunologist and associate professor in the Department of Microbiology, UAB School of Medicine, and Kharlampieva is a polymer and materials chemist and associate professor in the Department of Chemistry, UAB College of Arts and Sciences.
Their research, supported by two new JDRF Diabetes Foundation grants, “is a nice example of a truly multidisciplinary project that encompasses distinct areas of expertise including engineering, nanomaterials, immunology and islet transplantation,” said Fran Lund, Ph.D., professor and chair of Microbiology at UAB. “The project also melds basic science and engineering with the goal of developing better treatments for diabetes.”
“Our collaboration works because we have the same mindset,” Kharlampieva said of her collaboration with Tse. “We want to do good science.”
One of the chief jobs of pancreatic islets is production of insulin to regulate levels of blood sugar. In Type 1 diabetes, the β-cells that produce insulin are destroyed by an autoimmune attack by the body’s own immune system. To protect transplanted donor islets, researchers elsewhere have tried to coat islets with thick gels, or with coatings that bind covalently or ionically to the islets. Those approaches have had limited success.
Tse and Kharlampieva have taken a different approach, applying a gentler and much thinner coating of just five bilayers of biomimetic material about 30 nanometers thick. These layers act as a physical barrier that dissipates reactive oxygen species, and they also dampen the immune response. The thinness of the coat allows nutrients and oxygen easy passage to the cells.
“We did not expect the multilayers would show such a large, potential benefit,” Kharlampieva said of the immunomodulation shown by the bilayers.
The Tse-Kharlampieva collaboration got its start out of efforts to solve a problem in a UAB service to provide islets to national researchers — the islets often died or stopped secreting insulin during the three to five days of shipping. Kharlampieva was asked whether her bilayers might somehow protect the islets and preserve viability and functionality.
The bilayers are held together by hydrogen bonding, through an attraction between polar groups in the layers, which Kharlampieva calls a “friendlier approach” than covalent or ionic bonds. One of the layers, tannic acid, is a polyphenol that can scavenge destructive free radicals, much like the polyphenols found in green tea. Tse — who studies how oxidative stress contributes to islet dysfunction and autoimmune responses in Type 1 diabetes — wondered whether tannic acid’s ability to defuse radical oxygen species might help to lessen autoimmune dysregulation.
In collaborative research over more than five years, the UAB researchers showed that the answer was yes.
In a 2012 Advanced Functional Materials paper, Tse, Kharlampieva and colleagues found that:
• The bilayers, which include tannic acid, were able to wrap smoothly around a variety of mammalian pancreatic islets, and they maintained high chemical stability
• The coated islets retained viability and β-cell function in vitro for at least 96 hours
• Hollow shells of the bilayers suppressed synthesis of the proinflammatory cytokines IL12-p70 by stimulated macrophages and interferon- γ by stimulated T cells
In a 2014 Advanced Healthcare Materials paper, the researchers further examined the immunomodulatory effect of the hydrogen-bonded multilayers, in the form of hollow shells. They showed that the bilayer shells have:
• Antioxidant properties, as demonstrated by the dissipation of proinflammatory reactive oxygen and nitrogen species
• Immunosuppressive properties, as demonstrated by attenuated production of proinflammatory cytokines interferon-γ and tumor necrosis factor-α by antigen-stimulated autoreactive CD4+ T cells
The next step for the UAB researchers is in vivo testing of xeno- and allotransplantation to see if the bilayer-coated pancreatic islets have decreased risk of graft rejection, while restoring control of blood sugar. Xenotransplantation is transplanting from one species to another, and allotransplantation is transplanting from one member of a species to a different member of the same species.
In a one-year, in vivo demonstration grant, the UAB researchers found that nano-coated mouse islets survived and functioned as long as 40 days in diabetic mice that lack working immune systems. “We showed that they do stay alive, and they function to regulate blood glucose,” Tse said.
Now Tse and Kharlampieva, supported by two new JDRF grants, are testing the survival and functioning of nano-coated islets from mice or pigs in diabetic mice with intact immune systems.
The pig islets come from their University of Alberta collaborator Greg Korbutt, Ph.D. Korbutt’s team in Edmonton, Canada, has shown that human islets transplanted into immunosuppressed patients with brittle diabetes can produce insulin independence. “They are the leader in islet transplantation and developed the Edmonton Protocol for novel immunosuppression,” Tse said.
Pig islets — in contrast to scarce supplies of human islets — offer an unlimited source of insulin-producing tissue.
In the UAB experiments, the mouse and pig islets are coated with four or five bilayers of tannic acid and either poly(N–vinylpyrrolidone) or poly(N–vinylcaprolactam) by UAB research scientist Veronika Kozlovskaya, Ph.D. Mouse islet collection and transplantation of mouse or pig islets into mice is performed by UAB research technician Michael Zeiger, who grew up in Indonesia learning surgical skills from his veterinarian father.
At UAB, Lund holds the Charles H. McCauley Chair of Microbiology.
The National Institutes of Health will fund six projects to identify biological factors that affect neural regeneration in the retina. The projects are part of the National Eye Institute (NEI) Audacious Goals Initiative (AGI), a targeted effort to restore vision by regenerating neurons and their connections in the eye and visual system. These projects will receive a total of $12.4 million over three years, pending availability of funds.
“Understanding factors that mediate the regeneration of neurons and the growth of axons is crucial for the development of breakthrough therapies for blinding diseases. What we learn through these projects will have a health impact beyond vision,” said Paul A. Sieving, M.D., Ph.D., director of NEI, part of NIH.
Most irreversible blindness results from the loss of neurons in the retina, which is the light-sensitive tissue in the back of the eye. Many common eye diseases, including age-related macular degeneration, glaucoma and diabetic retinopathy, put these cells at risk. Once these neurons are gone, humans have little if any capacity to replace them.
These six projects will add to the knowledge base from several recent key advances. Researchers recently reported a technique that increases the regenerative capacity of retinal axons in a mouse model of optic nerve injury, a model commonly used to study glaucoma and other optic neuropathies. Progress also has been made in identifying factors that either stimulate or inhibit regeneration of neurons required for vision. The newly-funded projects will further this area of research by identifying cues that guide axons to appropriate targets in the brain, allowing functional connections to re-establish between the eye and the visual processing system.
The six projects include:
Molecular discovery for optic nerve regeneration
Principal investigators: Jeffrey L. Goldberg, M.D., Ph.D., Andrew D. Huberman, Ph.D., Stanford University, Palo Alto, California; Larry Benowitz, Ph.D., Harvard University, Cambridge, Massachusetts; Hollis Cline, Ph.D., Scripps Research Institute, La Jolla, California
Goldberg and colleagues have demonstrated through a series of interventions in mice with optic nerve injury that they can successfully regenerate retinal ganglion cells axons, which form the optic nerve that transmits visual information from the retina to the brain. In this next research phase they hope to identify genes and proteins that help or hinder this ability of retinal ganglion cells to regenerate, grow axons to a target and become functional in mice. Promising molecular candidates will be investigated in longer-term animal studies designed to assess changes in the animals’ vision.
Screening for molecules that promote photoreceptor synaptogenesis
Principal investigators: Donald J. Zack, M.D., Ph.D., Johns Hopkins University, Baltimore; David Gamm, M.D., Ph.D., University of Wisconsin, Madison
Zack, Gamm, and their teams plan to study precursor photoreceptor cells derived from human stem cells to determine what factors help coax them into becoming fully developed and connected photoreceptor cells. They expect their studies to identify a list of small molecules and candidate genes that contribute to the ability of photoreceptor cells to home in on their appropriate target cells in the retina, known as bipolar cells. In a healthy eye, bipolar cells receive signals from photoreceptor cells across a synapse and then transmit this information either directly or indirectly to retinal ganglion cells. Generating appropriate synapses between photoreceptor and bipolar cells is an essential step in restoring vision through photoreceptor transplantation.
Evaluation of novel targets for retinal ganglion cell axon regeneration
Principal investigator: Stephen M. Strittmatter, M.D., Ph.D., Yale University, New Haven, Connecticut
Strittmatter and his team also are searching for genes that contribute to the regeneration of axons from retinal ganglion cells. Starting with 450 candidate genes, culled from more than 17,000, they will test each candidate in a mouse optic nerve injury model, to see if any act as mediators of regeneration. Positive genes will then be validated by looking to see if they are also active in the C. elegans worm, an indication that a gene’s function is preserved across species. The strongest gene candidates will then be analyzed in greater detail to better understand their molecular action.
Novel activators of regeneration in Muller glia
Principal investigators: Edward M. Levine, Ph.D.; James G. Patton, Ph.D.; David J. Calkins, Ph.D. Vanderbilt University School of Medicine, Nashville, Tennessee
Levine and his colleagues are investigating exogenous and endogenous factors—that is, factors with an external or internal origin—that contribute to the successful reprogramming of supportive cells in the retina called Muller glia. In zebrafish, Muller glia can give rise to photoreceptor cells after injury to the retina. First, the investigators plan to test a novel combination of pharmacological agents and genetic manipulation for the ability to reprogram Muller glia in mice. If the therapy is successful, they will then study the conditions that support regeneration by determining which genes are turned on or off in regenerating zebrafish and mouse Muller glia. A second component of their project will look at the role of exosomes, tiny cell-secreted vesicles commonly found in blood and other bodily fluids, in promoting regeneration.
Comparative transcriptomic and epigenomic analyses of Muller glia reprogramming
Principal investigators: David R. Hyde, Ph.D., University of Notre Dame, South Bend, Indiana; John D. Ash, Ph.D., University of Florida, Gainesville; Andy J. Fischer, Ph.D., Ohio State University, Columbus; Seth Blackshaw, Ph.D., and Jiang Qian, Ph.D., Johns Hopkins University, Baltimore
In zebrafish and chicks, retinal damage induces Muller glia to reprogram and re-enter the cell cycle to produce neuronal progenitor cells, which are capable of moving to damaged retinal tissue and turning into the missing neuronal cell types. While Muller glia can initiate a regenerative response in the damaged zebrafish and chick retinas, mammalian Muller glia cannot, thereby preventing retinal regeneration and restoration of vision in humans and other mammals. Hyde and his colleagues are comparing the capacity of Muller glia cells from zebrafish, chicks and mice to perform this type of reprogramming. From the Muller glia in each animal, they will determine what gene activity is upregulated or downregulated (transcriptomics), as well as look for modifications to the genomic DNA (epigenomics), during retinal development and in response to different forms of retinal damage. These types of cross-species comparisons are designed to detect differences in gene expression, as well as to identify potential regulators that control Muller glia reprogramming. This work will shed light on why some species possess the ability to regenerate their damaged retinas while humans cannot.
Novel targets to promote RGC axon regeneration: Insights from unique retinal ganglion cell cohorts
Principal investigators: Kevin Park, Ph.D.; Vance Lemmon, Ph.D.; Sanjoy Bhattacharya, Ph.D., University of Miami Miller School of Medicine
Park and Lemmon are using RNA sequencing in cultured mouse retinal ganglion cells to identify differences in the expression of genes in regenerative versus non-regenerative retinal ganglion cells. In parallel, Park and Bhattacharya will use mass spectrometry to determine what lipids (or fat molecules) may give subclasses of retinal ganglion cells more robust regenerative capacities. The researchers will then perform a set of experiments aimed at understanding the function of the genes found to be involved in regeneration. The most promising gene candidates will be used as a therapy aimed at regenerating the optic nerve in a mouse model with optic nerve injury.
Every day, millions of Americans with diabetes have to inject themselves with insulin to manage their blood-sugar levels. But less painful alternatives are emerging. Scientists are developing a new way of administering the medicine orally with tiny vesicles that can deliver insulin where it needs to go without a shot. Today, they share their in vivo testing results.
The researchers are presenting their work at the 252nd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,000 presentations on a wide range of science topics.
“We have developed a new technology called a CholestosomeTM,” says Mary McCourt, Ph.D., a leader of the research team. “A CholestosomeTM is a neutral, lipid-based particle that is capable of doing some very interesting things.”
The biggest obstacle to delivering insulin orally is ushering it through the stomach intact. Proteins such as insulin are no match for the harsh, highly acidic environment of the stomach. They degrade before they get a chance to move into the intestines and then the bloodstream where they’re needed.
Some efforts have been made to overcome or sidestep this barrier. One approach packages insulin inside a protective polymer coating to shield the protein from stomach acids and is being tested in clinical trials. Another company developed and marketed inhalable insulin, but despite rave reviews from some patients, sales were a flop. Now its future is uncertain.
McCourt, Lawrence Mielnicki, Ph.D., and undergraduate student Jamie Catalano — all from Niagara University — have a new tactic. Using the patented CholestosomesTM developed in the McCourt/Mielnicki lab, the researchers have successfully encapsulated insulin. The novel vesicles are made of naturally occurring lipid molecules, which are normal building blocks of fats. But the researchers say that they are unlike other lipid-based drug carriers, called liposomes.
“Most liposomes need to be packaged in a polymer coating for protection,” says Mielnicki. “Here, we’re just using simple lipid esters to make vesicles with the drug molecules inside.”
Computer modeling showed that once the lipids are assembled into spheres, they form neutral particles resistant to attack from stomach acids. Drugs can be loaded inside, and the tiny packages can pass through the stomach without degrading. When CholestosomesTMreach the intestines, the body recognizes them as something to be absorbed. The vesicles pass through the intestines, into the bloodstream, and then cells take them in and break them apart, releasing insulin.
The team has delivered multiple molecules with these vesicles into cells in the lab. To pack the most insulin into the CholestosomesTM, the researchers determined the optimal pH and ionic strength of the drug-containing solution. They then moved the most promising candidates on to animal testing. Studies with rats showed that certain formulations of CholestosomesTMloaded with insulin have high bioavailability, which means the vesicles travel into the bloodstream where the insulin needs to be.
Next, the team plans to further optimize the formulations, conduct more animal testing and develop new partnerships to move forward into human trials.
At some point in their lives, 15 percent of people with diabetes will develop a painful and hard-to-treat foot ulcer. Twenty-four percent of those affected will require a lower-leg amputation because of it. And, in some instances, what seems like a harmless sore might even lead to death.
A Northwestern University team has developed a new treatment for this severe and potentially deadly complication of diabetes. Called a “regenerative bandage,” the novel material heals diabetic wounds four times faster than a standard bandage and has the added benefit of promoting healing without side effects.
“Foot ulcers cause many serious problems for diabetic patients,” said Guillermo Ameer, professor of biomedical engineering in Northwestern’s McCormick School of Engineering and surgery in the Feinberg School of Medicine. “Some sores don’t heal fast enough and are prone to infection. We thought that we could use some of our work in biomaterials for medical applications and controlled drug release to help heal those wounds.”
An expert in biomaterials and tissue engineering, Ameer’s research was published online last week in the Journal of Controlled Release. Yunxiao Zhu, a PhD student in Ameer’s laboratory, is the paper’s first author. Northwestern Engineering’s Hao F. Zhang, associate professor of biomedical engineering, and Feinberg’s Robert Galliano, associate professor of surgery, also contributed to the work.
Diabetes can cause nerve damage that leads to numbness in the feet. A diabetic person might experience something as simple as a blister or small scrape that goes unnoticed and untreated because they cannot feel it to know that its there. As high glucose also thickens capillary walls, blood circulation slows, making it more difficult for these wounds to heal. It’s a perfect storm for a small nick to become a life-threatening sore.
Some promising treatments for these chronic wounds exist, but they are costly and can come with significant side effects. One gel, for example, contains a growth factor that has been reported to increase cancer risk with overuse.
“It should not be acceptable for patients who are trying to heal an open sore to have to deal with an increased risk of cancer due to treating the wound,” Ameer said.
Ameer’s laboratory previously created a thermo-responsive material — with intrinsic antioxidant properties to counter inflammation — that is able to deliver therapeutic cells and proteins. His team used this material to slowly release into the wound a protein that hastens the body’s ability to repair itself by recruiting stem cells to the wound and creating new blood vessels to increase blood circulation.
“We incorporated a protein that our body naturally uses to attract repair cells to an injury site,” Ameer said. “When the protein is secreted, progenitor cells or stem cells come to the wound and make blood vessels, which is part of the repair process.”
The thermo-responsive material is applied to the wound bed as a liquid and solidifies into a gel when exposed to body temperature. When the same amount of the protein was directly applied all at once, no benefit was observed. This demonstrates the importance of slow release from the thermo-responsive material. Ameer believes that the inherent antioxidant properties within the material also reduce oxidative stress to help the wound heal.
“The ability of the material to reversibly go from liquid to solid with temperature changes protects the wound,” Ameer said. “Patients have to change the wound dressing often, which can rip off healing tissue and re-injure the site. Our material conforms to the shape and dimensions of the wound and can be rinsed off with cooled saline, if needed. This material characteristic can protect the regenerating tissue during dressing changes.”
In collaboration with Zhang, Ameer imaged diabetic wounds to discover that they were much healthier after application of the regenerative bandage. The blood flow to the wound was significantly higher than in those without Ameer’s bandage.
“The repair process is impaired in people with diabetes,” Ameer said. “By mimicking the repair process that happens in a healthy body, we have demonstrated a promising new way to treat diabetic wounds.”
The largest study of its kind into type 2 diabetes has produced the most detailed picture to date of the genetics underlying the condition.
More than 300 scientists from 22 countries collaborated on the study, which analysed the genomes of more than 120,000 people with ancestral origins in Europe, South and East Asia, the Americas and Africa.
The findings, published today in Nature, identify several potential targets for new diabetes treatments, but also reveal the complexity of the disease that needs to be addressed by efforts to develop more personalised strategies for treatment and prevention.
Type 2 diabetes is a growing threat to global health, with one in 10 people either having the disease or predicted to develop it during their lifetime. For any given individual, the risk of developing this form of diabetes is influenced by the pattern of genetic changes inherited from their parents, and environmental factors such as levels of exercise and choice of diet.
A better understanding of precisely how these factors contribute to type 2 diabetes will enable researchers to develop new ways of treating and preventing this condition, as well as offering the prospect for targeting those treatments towards those most likely to benefit, and those least likely to suffer harm.
Previous studies have identified over 80 areas in the genome that are associated with type 2 diabetes. However, these studies focused on the role of common DNA differences that appear frequently in the population, and they generally stopped short of identifying exactly which DNA sequence changes, or which specific genes, were responsible for this risk.
Today’s study explored the impact of changes in the DNA sequence on diabetes risk at a more detailed level. Some individuals had their entire genome sequenced while for others, sequencing was restricted to the part of the genome that codes directly for proteins (the exome).
Scientists compared the genetic variation between individuals who had type 2 diabetes and those who did not. This allowed them to test the contribution made by rare, ‘private’ DNA differences, as well as those that are common and shared between people.
They found that most of the genetic risk of type 2 diabetes can be attributed to common, shared differences in the genetic code, each of which contributes a small amount to an individual’s risk of disease. Some researchers had thought that genetic risk would instead be dominated by rare changes, unique to an individual and their relatives.
This finding means that future efforts to develop a personalised approach to treatment and prevention will need to be tailored toward an individual’s broader genetic profile, non-genetic risk factors and clinical features.
Researchers also identified over a dozen type 2 diabetes risk genes where the DNA sequence changes altered the composition of the proteins they encode. This implicates those specific genes and proteins directly in the development of type 2 diabetes.
One such variant – in the TM6SF2 gene – has been shown to alter the amount of fat stored in the liver, which in turn results in an increase in the risk of type 2 diabetes. Discoveries such as these point to new opportunities for developing drugs that might interrupt the development of the disease.
Mark McCarthy, from the Wellcome Trust Centre for Human Genetics at the University of Oxford, one of three senior authors on the paper, said: “This study highlights both the challenges we face, and the opportunities that exist, in resolving the complex processes underlying a disease such as type 2 diabetes. In this study, we have been able to highlight, with unprecedented precision, a number of genes directly involved in the development of type 2 diabetes. These represent promising avenues for efforts to design new ways to treat or prevent the disease.”
Joint senior author Professor Michael Boehnke, Richard G Cornell Distinguished University Professor of Biostatistics, Director, Center for Statistical Genetics, University of Michigan School of Public Health, added: “Our study has taken us to the most complete understanding yet of the genetic architecture of type 2 diabetes. With this in-depth analysis we have obtained a more complete picture of the number and characteristics of the genetic variants that influence type 2 diabetes risk.”
Data and discoveries generated through this project are available through the type 2 diabetes genetics portal (www.type2diabetesgenetics.org) developed as part of the Accelerating Medicines Partnership.
Jason Flannick, co-lead author and Senior Group Leader at the Broad Institute of Harvard and MIT and Research Associate at the Massachusetts General Hospital, said: “Our study tells us that genetic risk for type 2 diabetes reflects hundreds or even thousands of different genetic variants, most of them shared across populations. This large range of genetic effects may challenge efforts to deliver personalised (or precision) medicine. However, to ensure that these challenges can be taken up by the wider research community, we have made the data from our study publicly accessible for researchers around the world in the hope that this will accelerate efforts to understand, prevent and treat this condition.”
A team from the University of Montreal Hospital Research Centre (CRCHUM) has discovered a novel link between chronic kidney disease and diabetes. When kidneys fail, urea that builds up in the blood can cause diabetes, concludes a study published today in the Journal of Clinical Investigation.
“We identified molecular mechanisms that may be responsible for increased blood glucose levels in patients with non-diabetic chronic kidney disease. Our observations in mice and in human samples show that the disease can cause secondary diabetes,” said Dr. Vincent Poitout, researcher, CRCHUM Director, and principal investigator of the study.
Chronic kidney disease is characterized by the progressive and irreversible loss of kidney function in filtering and eliminating toxins from the blood. Eventually, those affected must undergo dialysis or kidney transplantation to eliminate toxins from their bloodstream.
It is well known that type 2 diabetes is one of the causes of chronic kidney disease. The nephrologist Laetitia Koppe, who has just completed a postdoctoral fellow in Dr. Poitout’s laboratory, has proven that the opposite is also true. “About half of those affected by chronic kidney disease have abnormal blood sugar levels. I wondered why. We conducted experiments in mice and found impaired insulin secretion from pancreatic beta cells, as observed in diabetes. We observed the same abnormalities in samples of pancreatic cells from patients with chronic kidney disease,” explained Dr. Koppe.
The researchers highlighted the surprisingly toxic role of urea, a nitrogenous waste product normally filtered by the kidneys and excreted in urine. “In patients with chronic renal failure, the kidneys are no longer able to eliminate toxins. Urea is part of this cocktail of waste that accumulates in the blood. In nephrology textbooks, urea is presented as a harmless product. This study demonstrates the opposite, that urea is directly responsible for impaired insulin secretion in chronic kidney disease,” argued Koppe.
At the heart of pancreatic beta cells, Drs. Koppe and Poitout identified a particular protein, called phosphofruktokinase 1. “The function of this protein is altered by an increase in blood urea, which occurs in chronic kidney disease. Increased urea causes impaired insulin secretion from the pancreatic beta cells. This creates oxidative stress and excessive glycosylation of phosphofructokinase 1, which causes an imbalance of blood glucose and may progress to diabetes,” said Dr. Poitout, who is also professor at the University of Montreal and the Canada Research Chair in Diabetes and Pancreatic Beta-Cell Function.
The study is important because it reveals a link and rather novel mechanism between chronic kidney disease and diabetes. “Further studies are required to validate these findings in humans. But if our observations are confirmed, it will mean that patients with non-diabetic chronic kidney disease are at risk of developing diabetes. One might then suggest therapeutic approaches, such as taking antioxidants, which may protect pancreatic beta cells and reduce the risk of developing diabetes,” said Dr. Poitout.
contributed by Richard (Rick) Mills
Editor, Ahead of the Herd
As a general rule, the most successful man in life is the man who has the best information.
Paul Lacey was a researcher at Washington University when, in 1972, he cured some diabetic rats by transplanting the islet cells from healthy rats into diabetic ones.
Over the next two decades researchers made many attempts to apply the procedure to humans. Unfortunately no one was successful. By the early 1990’s most scientists had come to the conclusion that islet-cell transplantation was a lost cause.
Drs. James Shapiro, Jonathan Lakey and colleagues from the University of Alberta in Edmonton were successful at improving the treatment of a select group with severe diabetes through development of the Edmonton protocol in the late 1990s.
The Edmonton Protocol is a method of transplantation of pancreatic islets into the portal vein of the recipient’s pancreas. These pancreatic islets are sourced/extracted from pancreases removed from recently deceased adults.
Each recipient receives islets from one to three donors. The islets are infused into the patient’s portal vein, and are then protected from the recipient’s immune system through the use of two immunosuppressant drugs as well as an antibody drug specifically used in transplant patients.
Since 2000 close to a thousand people have received islet transplants – but by five years after the procedure, on average fewer than 10% of all patients are free of daily insulin supplementation. Thus, while islet cell transplantation has demonstrated exciting success and the potential for cell therapy as a treatment for diabetes has great promise, further technology developments are required.
Exactly what is Diabetes?
Diabetes is a condition in which the sugar levels in the blood are too high on a constant basis. Without tight blood sugar control to normal levels, this can result in severe long term medical consequences.
Much of the food one eats is broken down into a simple sugar called glucose. In response to a rise in glucose levels after a meal the islet’s beta-cells in the pancreas detect blood glucose levels and secrete insulin into the blood. Insulin acts to open the gates of cells allowing the glucose to move from the blood stream into the cells where it can be utilized for energy.
A Type 1 diabetes diagnosis means the pancreatic beta cells that read glucose levels and secrete insulin have been damaged or destroyed. Thus, glucose cannot move from the bloodstream into the cells allowing blood sugars to rise.
A Type 2 (insulin resistance) diabetes diagnosis is a far more common verdict for people than Type 1. Insulin resistance occurs as a result of chronically elevated blood sugar and insulin levels. These elevated levels of sugar and insulin have the effect of “numbing” the cellular processes which move the sugar from the blood stream to the cells – the body cannot respond to the insulin “requests” to move blood sugar into the cells. Approximately 27% of the people who start out as Type 2 diabetics, will, in the future require insulin injections similar to Type 1 diabetics.
Diabetic complications, which occur even in individuals taking insulin injections, include irreversible damage to the heart, blood vessels, eyes, kidneys, skin, feet and hearing. In individuals taking insulin injections to reduce blood sugar levels, severe hypoglycemia from a single injection of too much insulin, can cause organ failure, coma and death.
Diabetes is not considered a high mortality condition, but it is a major risk factor for other causes of death and has an extremely high attributable burden of disability, for example; 2% of people with diabetes become blind, about 10% develop severe visual impairment, and 50% of people with diabetes die of cardiovascular disease.
Standard of Care
The Standard of Care for patients with reduced or missing critical hormones or proteins, such as insulin, is often monitoring and injecting these proteins multiple times a day.
A search has been on for an alternative site for islet transplantation as well as for an optimal medical device in which to implant the islets (therapeutic cells). Several subcutaneous devices have previously been developed for islet transplantation but from a preclinical and clinical perspective the results from these products have been generally disappointing.
Current cell therapy is limited to poor cell survival, inappropriate delivery of hormones and a lack of available donors and cells. At this time there is no approved device to house and protect therapeutic cells in the body.
Sernova Corp is a Phase I/II clinical stage company developing medical technologies for the treatment of chronic debilitating metabolic diseases to replace proteins or hormones in short supply within the body.
The first proprietary platform technology is the Cell Pouch System™. Think of SVA’s Cell Pouch System™ as a potential natural insulin producing pump with the added benefit of fine-tuned glucose control with no need to replenish the insulin. When placed under the skin and filled with islets it can develop pancreas-like characteristics taking over normal blood glucose control. The device uniquely forms highly vascularized tissue chambers for the placement, survival and function of therapeutic cells. Insulin producing islets transplanted in the device have been proven to become connected to microvessels and able to produce all of the regulatory hormones to control diabetes.
Sernova is exploring the additional utility of the Cell Pouch System™ as an enabling platform for a range of therapeutic cell types and diseases. The technology could be used for a patient’s own cells (autograft), or a donor’s cells (allograft).
The therapeutic cells placed into the device may also be cells that can be a source to treat millions of patients such as stem cell derived therapeutic cells (stem cells have the ability to differentiate into other cell/tissue types) or xenogeneic (derived or obtained from an organism of a different species) cells.
Sernova’s products are also designed to allow for multiple market expansion opportunities within each therapeutic area. For example, the technology would be beneficial if it provided a simple reduction in the number of daily therapeutic injections a patient must take; however, there is the possibility that it could even essentially ‘cure’ the disease through natural release and regulation of the therapeutic proteins or hormones.
Sernova’s products are uniquely focused on those diseases in which a protein, hormone or factor, missing or in short supply in the body, could be replaced by therapeutic cells which release those factors into the bloodstream.
Diabetes and hemophilia are but two of the multibillion dollar market opportunities where such treatments could lead to:
• A significant improvement in the quality of patient’s lives
• Reducing health care costs
• Potentially reduce the devastating side effects of disease
While other scientific laboratories around the world were advancing stem cell technologies which, if successful, would provide sources of therapeutic cells for various clinical applications, Sernova was in parallel working on their proprietary, scalable, implantable medical device (Cell Pouch System™) that creates a natural environment for the survival and function of these therapeutic cells.
Sernova is in the forefront of such technologies.
About 347 million people worldwide have diabetes. The World Health Organization (WHO) projects that diabetes will be the 7th leading cause of death in 2030.
July 12, 2016 – Sernova Corp. a clinical stage company developing disruptive regenerative medicine technologies for the long-term treatment of chronic diseases including diabetes and hemophilia, is pleased to announce today it has entered into a research funding agreement with JDRF, the leading global organization funding and advocating for type 1 diabetes (T1D) research.
The purpose of the funding is to advance human clinical trials of Sernova’s
Cell Pouch System(TM) (CPS) technologies for treatment of hypoglycemia unawareness patients with severe type 1 diabetes. T1D is a life-threatening disease in which the body’s immune system mistakenly attacks and kills the pancreatic cells that produce insulin—a hormone that is essential for life because of its role to help the body use glucose.
JDRF will provide Sernova up to US$2.45 million to support a clinical trial at a major transplantation center in the United States. The goal of the study is to provide patients with hypoglycemia unawareness a novel cell therapy treatment utilizing Sernova’s proprietary, highly vascularized, cell macroencapsulated implantable and scalable device to reduce or eliminate the need for injections of exogenous insulin.
“Sernova’s progression to human clinical trials is an incredible accomplishment in the global diabetes research agenda. I am particularly proud of this trial being a part of the JDRF portfolio because it supports advancements of the best and brightest research minds in Canada at Sernova. Also, this is a shining example of the international collaboration fostered by projects funded by JDRF. Working together with our global partners, we can accelerate this type of transformative research and ensure it becomes available for the T1D community.” Dave Prowten, President and CEO of JDRF Canada.
Patients with hemophilia A have a defective gene for factor VIII. Patients receive prophylaxis factor replacement therapy two to three times a week. Prophylactic therapy (prevention therapy) involves three infusions of Factor VIII each week at a hospital at a cost of about USD$200,000/yr.
December 21, 2015 – Sernova Corp. announced today that the European Commission’s Horizon 2020 program has awarded a Euro 5.6M ($8.5M CAD) grant to a consortium consisting of Sernova Corp and five European academic and private partners to advance development of a GMP clinical grade Factor VIII releasing therapeutic cell product in combination with Sernova’s Cell Pouch(TM) for the treatment of severe hemophilia A
February 16, 2016 – Sernova Corp. announced today it has received its initial € 566,500 ($875,000 CDN) installment of non-dilutive funds from the HemAcure Grant funded by the EU Horizon 2020 Program. Sernova will use the payment to fund activities related to the development of a GMP clinical grade Factor VIII releasing therapeutic cell product combined with Sernova’s Cell Pouch(TM) to treat severe hemophilia A, a serious genetic bleeding disorder caused by missing or defective factor VIII in the blood stream.
“We are excited that the HemAcure consortium partners, a group developing a therapeutic that is highly disruptive to the current standard of care treatments for hemophilia A, are already working diligently to advance the program. Together, we are working to address, with a sense of urgency, the critical challenges posed by severe hemophilia A.” Dr. Philip Toleikis, Sernova President and CEO.
Since late December 2015, Sernova and its collaborative partners have announced funding of joint research hemophilia and diabetes collaborations totaling Cdn$11,780,000.00.
Individually each of these collaborations is massive validation of Sernova’s technology. Taken together they show a company on the cusp of being THE paradigm changer in science and they highlight Sernova’s capability to profoundly disrupt current standard of care.For this reason Sernova Corp has to be on everyone’s radar screen.
Richard (Rick) Mills
Richard owns shares of Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH)
Richard lives with his family on a 160 acre ranch in northern British Columbia and is the owner of Aheadoftheherd.com.
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