HemAcure and Sernova, A Big Deal

Richard (Rick) Mills
Ahead of the Herd

As a general rule, the most successful man in life is the man who has the best information

When most of us suffer a cut cells in the blood, called platelets, go to where the cut is, plug the hole and stop the bleeding. While the platelets are plugging the hole they release chemicals that attract more of the ‘sticky’ platelets and twelve (numbered using Roman numerals I through XII) proteins in the blood known as clotting factors are activated. These proteins mix with the platelets to form fibers which make the clot stronger and stop the bleeding.

Having too little of factors VIII (8) or IX (9) is what causes hemophilia. A person with hemophilia will lack only one factor, either factor VIII or factor IX, but not both. There are two major kinds of hemophilia: hemophilia A, which is a factor VIII deficiency; and hemophilia B, which is a factor IX deficiency.

Hemophilia is a genetic disorder which means it’s the result of a change in genes that was either inherited (passed on from parent to child) or occurred during development in the womb. Although it is mostly passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene. All races and ethnic groups are equally affected by hemophilia A. The disease almost always affects males but can also affect females.

Many people believe that hemophiliacs bleed a lot from minor cuts but external wounds are usually not that serious. Much more serious is internal hemorrhaging that can take place in joints (especially knees, ankles and elbows) and into tissues and muscles. Bleeding can also occur in vital organs putting a hemophiliac’s life in danger.

Although effective treatment of the symptoms is available, there is no cure for hemophilia A at present and therapy has to be individualized to specific patients. Patients have to get lifelong infusions with recombinant factor VIII (rFVIII) several times a week to compensate for the missing clotting factor.

The global total hemophilia market was valued at US$ 9.3 billion in 2015. Approximately 20,000 people in the United States, 10,000 in Europe and approximately 2,500 in Canada have a moderate or severe form of hemophilia A. Annual costs for the treatment of the disease for each patient may range from US$60,000 to US$260,000 for a total cost of between $2-5B per year just in North America and Europe.

Grand View Research

The Horizon 2020 program

Horizon 2020 is the largest European Union (EU) research and innovation program ever undertaken with nearly €80 billion of funding available over the seven years between 2014 to 2020. Horizon 2020 promises breakthroughs, discoveries and world firsts by taking great ideas from the lab to the market, for example in the field of personalized medicine providing novel therapies such as gene or cell therapy.

HemAcure project, a novel personalized medicine curative therapy

An international research consortium, under the name HemAcure unites scientific academic institutions from Germany, Italy, the UK and Sernova Corp from Canada.

The following institutions are involved in HemAcure:

  • ARTTIC, a Munich-based enterprise that specializes in the management of EU-funded collaborative research projects, is in charge of project management.
  • The Department of Tissue Engineering and Regenerative Medicine of the Wuerzburg University Hospital is responsible for isolating the cells.
  • The Università del Piemonte Orientale (Italy) is developing, optimizing and performing the gene correction of the patient cells for expression of the Factor VIII therapy.
  • Scientists from Loughborough University (UK) are focussing on the manufacturing process and safety testing.
  • Sernova a Canadian public company, is responsible for conducting the preclinical safety and efficacy studies with the Factor VIII producing cells in its proprietary Cell Pouch™ using a model of hemophilia developed by consortium partner Universita del Piemonte Orientale (Italy) in preparation for clinical trials.
  • The quality management (GMP processes) is being monitored by IMS – Integrierte Management Systeme in Heppenheim, Germany. The company acts as a point of contact for international projects in the pharmaceutical and medical engineering sector.

The overall objective of the HemAcure project is to develop and refine the tools and technologies for a novel, curative ex vivo (outside the body) prepared cell based therapy to treat hemophilia A that should ultimately lead to improved quality of life for patients. The EU’s Horizon 2020 programme has stage funded the HemAcure project with €5.5 million (Cdn$8.06M, US$6.3). The most recent tranche of funding has just been approved based on the encouraging results to date.

The consortium’s idea: A personalized medicine solution using the patients’ own cells (remember each patient has to have individualized therapy) which are genetically modified outside the body to produce the missing clotting factor using precursor cells of endothelial cells flowing in the bloodstream. After modification these cells are transplanted back into the patient’s body in Sernova Corp’s Cell Pouch™.

After Sernova’s Cell Pouch™ is implanted in the body and forms its unique vascularized tissue chambers, the genetically modified cells are then transplanted into the vascularized chambers and are expected to continuously produce the clotting factor and release it into the bloodstream for a long period of time. This should mitigate the disease’s impact noticeably, increase the patients’ quality of life and reduce the overall cost of therapy.

Sernova

Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), is a Canadian publically traded, clinical stage, regenerative medicine company developing an implantable, scalable device, the Cell Pouch System™ and therapeutic cells for the treatment of diseases such as diabetes, and hemophilia.

Sernova’s Cell Pouch™ forms a natural vascularized environment for long-term survival and function of the therapeutic cells which release into the bloodstream required but missing proteins or hormones.

Sernova’s Cell Pouch™ technology would be beneficial if it provided a simple reduction in the number of 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 has developed its proprietary highly innovative Cell Pouch technologies for the placement and long-term survival and function of immune protected therapeutic cells. It has proven to be safe and efficacious in multiple small and large animal preclinical models and has demonstrated safety alone and with therapeutic cells in a clinical trial in humans for another therapeutic indication (diabetes – editor). We believe the Cell Pouch platform is the first such patented technology proven to become incorporated with blood vessel enriched tissue-forming tissue chambers without fibrosis for the placement and long-term survival and function of immune protected therapeutic cells.” Sernova News Release, Marketwire – July 24, 2017

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. Below is a HemAcure consortium approved news release issued by Sernova Corp. on Monday July 24, 2017.

It’s your authors opinion ‘relatively unknown’ is a term that will shortly no longer apply to Sernova Corp.

Sernova-HemAcure Consortium Announce Significant Progress in Development of ‘First in World’ Regenerative Medicine Therapy for Treatment of Hemophilia A Patients

Breakthrough scientific progress is made in development of a disruptive personalized regenerative medicine therapy within Sernova’s Cell Pouch(TM) for treatment of Hemophilia A validated by European Commission’s confirmation of next stage of funding of the €5.6Million EU Horizon 2020 Grant Award to the HemAcure Consortium

LONDON, ONTARIO – (Marketwire – July 24, 2017) – Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH), a clinical stage regenerative medicine company, announced today significant scientific progress achieved in the development of a ‘first in world’ personalized regenerative medicine therapy for the treatment of Hemophilia A patients by the HemAcure Consortium and confirmation of the second phase of funding of the Consortium by the European Commission.

The therapy being developed by international scientific Consortium members consisting of three European academic institutions, an enterprise for quality management and Sernova Corp is to treat severe Hemophilia A, a serious genetic bleeding disorder caused by missing or defective clotting factor VIII in the blood stream. This therapy consists of Sernova’s implanted Cell Pouch(TM) device transplanted with therapeutic cells, corrected to produce Factor VIII at a level sufficient to significantly reduce the side effects of the disease and improve patient quality of life.

“The international HemAcure Consortium team members are pleased with the ground breaking scientific advances achieved at this point and are on track for this regenerative medicine solution to advance into human clinical evaluation,” remarked Dr. Philip Toleikis, Sernova President and CEO.

Toleikis added, “Sernova’s Cell Pouch platform technologies are achieving important world first milestones in both diabetes and now hemophilia, two significant clinical indications which are being disrupted by its regenerative medicine approach aimed at significantly improving patient quality of life.”

“We are thrilled with the approval by the European Union of the next stage of funding for the HemAcure program based on our quality interim report. This is a strong validation of the Consortium’s dedication and teamwork and the importance of this regenerative medicine approach,” said Dr. Joris Braspenning, HemAcure Program Coordinator.

In summary, the following ground-breaking developments have been achieved by the Consortium:

  • A reliable procedure has been implemented to isolate and maintain required endothelial cells from a sample of the patient’s blood.
  • Using a novel gene correction process, the cells have been corrected and tuned to reliably produce the required Factor VIII to treat Hemophilia A.
  • The cells have been successfully scaled up to achieve the required therapeutic number, and cryopreserved for shipping and future transplant into the implanted Cell Pouch.
  • A preliminary study confirmed survival of the Factor VIII corrected human cells injected into the hemophilia model, achieving sustained therapeutic Factor VIII levels. This preliminary work is being used to aid in dosing of these cells in the Cell Pouch.
  • Safe Cell Pouch surgical implant and cell transplant procedures have been developed in the hemophilia A model in preparation for use in hemophilia patients.
  • Development of Cell Pouch vascularized tissue chambers suitable for Factor VIII producing cell transplant has been demonstrated in the hemophilia A model, expected to mimic the predicted findings in human patients.
  • In combination, this work is in preparation for safety and efficacy studies of the human hemophilia corrected Factor VIII producing cells in the Cell Pouch in a preclinical model of hemophilia.

This combination of advances by the HemAcure team represents a ‘first in world’ achievement towards developing a regenerative medicine therapy for the treatment of severe hemophilia A patients.

“In this regard, these fundamental advancements have set the stage for further optimization and implementation of cell production processes under controlled GMP conditions,” stated Martin Zierau, IMS member consortium team leader responsible for coordination of GMP processes.

With Factor VIII corrected cells, studies are ongoing to optimize cell dosing within the Cell Pouch and for study of safety and efficacy of hemophilia corrected Factor VIII cells in the hemophilia model. These studies are in support of the current extensive regulatory package already assembled for the Cell Pouch in anticipation of human clinical evaluation of the Cell Pouch with hemophilia corrected Factor VIII producing cells.

A big deal

Any discussions regarding advancing HemAcure’s plan, and more funding from Horizon 2020, had to be centered around success in these three areas:

  • CELLS ARE PRODUCING FACTOR VIII: The Consortium has successfully developed the process for isolating and maintaining the required cells from a sample of patient’s blood. Using a special technique these cells have been corrected and tuned to produce Factor VIII on a constant basis.
  • CORRECTED CELLS HAVE BEEN SCALED UP: The corrected cells have then been multiplied to demonstrate that the required number of cells can be produced. After testing, batches of corrected cells have been frozen, stored for later transplantation and successfully shipped, thawed and recovered. With further optimization and GMP production, this being the process anticipated to be used for future treatment of patients with hemophilia A.
  • CELLS PRODUCING THERAPEUTIC BLOOD LEVELS OF FACTOR VIII: In further preclinical tests, in a preliminary study, Factor VIII producing cells have been shown to produce therapeutic blood levels of Factor VIII. Studies have already shown that the Cell Pouch can produce vascularized tissue chambers in the hemophilia model and further studies will optimize dosing of hemophilic patient corrected cells that will then be transplanted into the Cell Pouch™ for evaluation of safety and efficacy in the preclinical model of hemophilia.

Conclusion

Being that all the companies in the HemAcure consortium are private, except SVA, and that they plan on ‘bringing breakthroughs, discoveries and world firsts from the lab to the market’ might not Sernova be a great way to leverage this in your portfolio?

And SVA is no one trick pony, the company is a leader in the regenerative space with their Cell Pouch™ and upon FDA clearance plan to initiate clinical trials in the United States for diabetes – expected to start patient enrollment this fall.

Add in developing local immune protection technology within the Cell Pouch™ and the company’s very own glucose responsive stem cell technology, you can see why your author thinks Sernova Corp might just be the best regenerative medicine pure play out there.

All of these reasons are why Sernova Corp. is on my radar screen. Is SVA on yours?

If not, maybe it should be.

Richard (Rick) Mills

aheadoftheherd.com

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UC research examines lung cell turnover as risk factor & target for treatment of influenza pneumonia

Influenza is a recurring global health threat that, according to the World Health Organization, is responsible for as many as 500,000 deaths every year, most due to influenza pneumonia, or viral pneumonia. Infection with influenza most typically results in lung manifestations limited to dry cough and fever, and understanding how the transition to pneumonia occurs could shed light on interventions that reduce mortality. Research led by University of Cincinnati (UC) scientists takes a different approach to investigating how influenza spreads through the lungs by focusing on how resistant or susceptible cells lining the airway are to viral infection.

The work published today in the Proceedings of the National Academy of Sciences (PNAS) shows how stimuli that induce cell division in the lung promote spread of influenza from the airway to the gas exchanging units of the lung, known as the alveoli. The UC study also demonstrates that interventions that prevent alveolar cells from dividing reduce influenza mortality in animal models, suggesting a potential prophylactic and/or therapeutic strategy for influenza pneumonia.

“Almost all research into susceptibility or resistance to influenza focuses on host immune responses,” says Nikolaos Nikolaidis, PhD, research scientist in the Division of Pulmonary, Critical Care and Sleep Medicine in the Department of Internal Medicine at the UC College of Medicine and lead author on the paper. “Our approach was to examine factors that influence the vulnerability of alveolar cells to influenza infection, separate from how the immune system is dealing with the virus.”

“Less than 1 percent of alveolar cells are actively dividing at any given time in the healthy lung, rendering it naturally resistant to influenza infection,” says Frank McCormack, MD, Gordon and Helen Hughes Taylor Professor of Internal Medicine and director of the Division of Pulmonary, Critical Care and Sleep Medicine and senior author on the paper. “Recovery from lung injury due to supplemental oxygen therapy, cigarette smoke or scarring lung diseases is associated with expression of growth factors that result in multiplication of lung cells. Our work demonstrated that these mitogenically stimulated cells are rich targets for influenza infection while they are dividing.”

The researchers found that when sirolimus, which is FDA-approved for use as an anti-growth agent for the rare lung disease, lymphangioleiomyomatosis (LAM), was given to influenza-infected animal models, it prevented alveolar cells from dividing, and as a result, protected the mice from viral pneumonia and death.

“Although sirolimus also has off target immunosuppressive properties that could potentially pose added risks of side effects in virus-infected patients, trials of inhaled sirolimus could lead to approaches that do not entail systemic exposure,” says McCormack.

The McCormack lab expressed optimism that this observation has the potential to ultimately inform understanding of other unexplained risk factors for influenza, including very young age and pregnancy, and perhaps even to change medical management, such as more judicious use of supplemental oxygen in patients admitted with suspected viral pneumonia. Further, the team has hopes that the research could lead to a paradigm shift in the approach to therapy.

Nikolaidis says the next step in this research is to further explore why the multiplying alveolar epithelial cell is a better target for influenza. “Is it because the virus gets into the dividing cell more easily, because multiplying stimuli expand the pool of cellular machinery used by the virus to replicate, or because proliferation is associated with a reduction in innate cellular defenses? We are anxious to explore these and other potential mechanisms of viral susceptibility,” he adds.

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

Glioblastoma is the most malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is an enzyme that is highly expressed in glioblastoma, especially in cancer stem cells.

The research group of Professor Masaharu Noda and Researcher Akihiro Fujikawa of the National Institute for Basic Biology (NIBB) showed that the enzymatic activity of PTPRZ is requisite for the maintenance of stem cell properties and tumorigenicity in glioblastoma cells. PTPRZ knockdown strongly inhibited tumor growth of C6 glioblastoma cells in a mouse xenograft model. In addition, the research team discovered NAZ2329, an allosteric inhibitor of PTPRZ, in collaboration with ASUBIO Pharma Co. Ltd.. NAZ2329 efficiently suppressed stem cell-like properties of glioblastoma cells in culture, and tumor growth in C6 glioblastoma xenografts. These results indicate that pharmacological inhibition of PTPRZ is a promising strategy for the treatment of malignant gliomas.

Radiation Therapy Prior to Surgery Reduces the Risk of Secondary Tumors in Early-Stage Breast Cancer Patients

Breast cancer patients receiving neoadjuvant radiation therapy have improved cancer-free survival over adjuvant radiation

Moffitt Cancer Center researchers launched a first of its kind study comparing the long-term benefits of radiation therapy in women with breast cancer either before surgery (neoadjuvant) or after surgery (adjuvant). Their study, published in the June 30 issue of Breast Cancer Research, found that patients who have neoadjuvant radiation therapy have a significantly lower risk of developing a second primary tumor at any site.

The majority of patients who have early stage breast cancer have surgery to remove their tumor or a complete mastectomy. Surgery is commonly followed by radiation therapy, which has been shown to increase relapse-free survival. However, in some cases, patients may require neoadjuvant radiation therapy to decrease the size of the tumor before surgery.  Currently, there are no studies that have analyzed the long-term effects of neoadjuvant radiation therapy on breast cancer patients.

Moffitt researchers compared the overall survival and the time to diagnosis of a second tumor, if any, of 250,195 breast cancer patients who received either neoadjuvant or adjuvant radiation therapy. They analyzed patient outcomes from a National Cancer Institute (NCI) registry database of cancer incidence and survival rates in the United States.  They included female patients in the analysis who were diagnosed between 1973 and 2011 with early-stage breast cancer. The analysis included 2,554 women who received localized neoadjuvant breast radiation therapy before surgery and 247,641 women who received localized adjuvant breast radiation therapy after surgery.

The researchers discovered that among the breast cancer patients who tested positive for the estrogen receptor (ER) biomarker, patients who had neoadjuvant radiation therapy had a significantly lower risk of developing a second primary tumor than patients who had adjuvant radiation therapy. This was true for patients who underwent both partial and complete mastectomies.  The researchers found that delaying surgery due to neoadjuvant radiation therapy was not a detriment to survival.

A number of recent studies have suggested that radiation therapy may re-educate and stimulate the immune system to target cancer cells. “The observed benefit of neoadjuvant radiation therapy aligns with the growing body of literature of the immune activation effects of radiation, including shrinking of untreated metastases outside the radiation field,” explained Heiko Enderling, Ph.D., associate member of Moffitt’s Integrated Mathematical Oncology Department.

T-cells lacking HDAC11 enzyme perform more effectively in destroying cancer cells

Researchers at the George Washington University (GW) Cancer Center have discovered a new role for the enzyme, histone deacetylase 11 (HDAC11), in the regulation of T-cell function.

T-cells can infiltrate tumors with the purpose of attacking the cancer cells. However, prior studies have found that the T-cells group around the tumor, but do not perform the job that they are meant to.

“The goal of the T-cell is to destroy the cancer tumor cells,” Eduardo M. Sotomayor, MD, director of the GW Cancer Center and senior author of the study, explained. “We wanted to look at and understand the mechanisms that allowed crosstalk between the tumor and the T-cells that stopped the T-cells from doing their job.”

The recent research, published in the journal Blood, centered on the discovery of “epigenetic checkpoints” in T-cell function in an effort to explain how and why these cells are modified to behave differently. The study found that when HDAC11 was removed the T-cells, they were more primed to attack the tumor.

More importantly, this research highlights that HDAC11, which was the last of 11 HDAC to be discovered, should be treated as an immunotherapeutic target.

While the study focused on the T-cells around a lymphoma tumor, this research is pertinent to all types of cancer. The goal for the team was to find a way to activate the T-cells so that they could destroy the tumor. However, the process of cell activation does need to be refined and handled carefully.

“We don’t want T-cells to be easily activated, as they can cause harm to the host — the patient. So we want to look at possible methods and therapies to activate the T-cells when they need to work,” said Sotomayor.

“The next step is to perform preclinical studies with specific inhibitors of HDAC11 alone and in tandem with other existing immunotherapies, such as anti-PD1/anti-PDL1 antibodies, in order to find the most potent combination. Our goal is to make the T-cells better at destroying cancer tumors.”

This study represents a step forward in understanding the underlying mechanisms of T-cell function and epigenetic regulation of the HDAC11 enzyme.

Targeting ‘broken’ metabolism in immune cells reduces inflammatory disease

The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune diseases and sepsis.

In a study published this week in the journal Nature Communications, they explain how blocking a single enzyme enabled them to reprogram macrophages – the immune cells which are activated in inflammatory conditions – to calm their activity and reduce inflammation in rats and mice with human-like disease.

At the heart of the research is the Krebs cycle, a complex loop of reactions which cells use to feed on sugar and generate molecules of ATP, the universal energy currency for cells.

In recent years, research has shown that the usual pathway is interrupted in immune cells such as macrophages, leading to a broken Krebs cycle.

“In immune cells that have to fight invaders, the metabolism is diverted from its usual cycle to make compounds that fight microbes,” explained Dr Jacques Behmoaras, from the Department of Medicine at Imperial, who led the research.

Dr Behmoaras added: “What we have found is that there’s an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds. If you block that enzyme, you block that specific branch of their metabolism, and make the cells cause less damage during inflammation.”

Using human macrophages, the researchers found that an enzyme called BCAT1 was pivotal in reprogramming macrophages. When the cells were activated – by exposing them to molecules found on the surface of bacteria – BCAT1 interfered with their usual metabolic pathways, and regulated another enzyme, responsible for producing bacteria-killing chemicals.

They used an experimental compound called ERG240, developed by Ergon Pharmaceuticals, a small biotech company based in the US. ERG240 resembles the amino acid leucine, one of the building blocks of proteins, which is linked together by BCAT1. By flooding the cells with ERG240 they were able to jam up BCAT1 and block its action, so stopping the metabolism being diverted and ‘fixing’ the broken Krebs cycle. What’s more, the compound was shown to work in animal models of inflammation, without toxic side effects.

The team found that when ERG240 was given to mice with symptoms of rheumatoid arthritis, it reduced the inflammation in their joints by more than half while protecting the integrity of their joints. Similarly, in a rat model of severe kidney inflammation, they found that ERG240 improved kidney function by reducing the number of macrophages flooding into the affected tissue to cause inflammation.

Dr Behmoaras states that although the research is still at an early stage, there is potential for treating inflammatory conditions in patients by targeting the metabolic activity in immune cells. The team believes that BCAT1 works together with other key enzymes of the Krebs cycle, which could themselves provide targets for therapy.

However, one of the key challenges in developing a therapy would be in finding the balancing point: calming the immune cells enough such that they reduce inflammation, but enabling them to react to microbial invaders.

“I think this ability to regulate metabolism in cells could have an effect on many human diseases,” said Dr Behmoaras. “Manipulating cell activity in inflammatory diseases where macrophages have a role, could have important therapeutic benefits.

“Our next step is to understand how other enzymes in the cycle are involved, to see if there is any possibility to block them and have similar effects. Understanding the complex metabolic circuits of these immune cells is a huge task. We will need to tackle this before we can manipulate cell activity and influence disease.

“This is a growing field of research with exciting discoveries ahead.”

Stem Cells May Be The Key To Staying Strong In Old Age

University of Rochester Medical Center researchers have discovered that loss of muscle stem cells is the main driving force behind muscle decline in old age in mice. Their finding challenges the current prevailing theory that age-related muscle decline is primarily caused by loss of motor neurons. Study authors hope to develop a drug or therapy that can slow muscle stem cell loss and muscle decline in the future.

As early as your mid 30’s, the size and strength of your muscles begins to decline. The changes are subtle to start — activities that once came easily are not so easy now — but by your 70’s or 80’s, this decline can leave you frail and reliant on others even for simple daily tasks. While the speed of decline varies from person to person and may be slowed by diet and exercise, virtually no one completely escapes the decline.

“Even an elite trained athlete, who has high absolute muscle strength will still experience a decline with age,” said study author Joe Chakkalakal, Ph.D., assistant professor of Orthopaedics in the Center for Musculoskeletal Research at URMC.

Chakkalakal has been investigating exactly how muscle loss occurs in aging mice in order to figure out how humans might avoid it.

In a study, published today in eLife, Chakkalakal and lead author Wenxuan Liu, Ph.D., recent graduate of the Biomedical Genetics Department at URMC, define a new role for stem cells in the life long maintenance of muscle. All adults have a pool of stem cells that reside in muscle tissue that respond to exercise or injury — pumping out new muscle cells to repair or grow your muscles. While it was already known that muscle stem cells die off as you age, Chakkalakal’s study is the first to suggest that this is the main driving factor behind muscle loss.

To better understand the role of stem cells in age-related muscle decline, Chakkalakal and his team depleted muscle stem cells in mice without disrupting motor neurons, nerve cells that control muscle. The loss of stem cells sped up muscle decline in the mice, starting in middle, rather than old age. Mice that were genetically altered to prevent muscle stem cell loss maintained healthier muscles at older ages than age-matched control mice.

At the same time, Chakkalakal and his team did not find evidence to support motor neuron loss in aging mice. Very few muscle fibers had completely lost connection with their corresponding motor neurons, which questions the long-held and popular “Denervation/Re-innervation” theory. According to the theory, age-related muscle decline is primarily driven by motor neurons dying or losing connection with the muscle, which then causes the muscle cells to atrophy and die.

“I think we’ve shown a formal demonstration that even for aging sedentary individuals, your stem cells are doing something,” said Chakkalakal. “They do play a role in the normal maintenance of your muscle throughout life.”

Chakkalakal is building on this discovery and searching for a drug target that will allow him to maintain the muscle stem cell pool and stave off muscle degeneration as long as possible and he hopes this discovery will help move the field forward.

Promising new therapeutic approach for debilitating bone disease

An Australian-led research team has demonstrated a new therapeutic approach that can re-build and strengthen bone, offering hope for individuals with the debilitating bone cancer, multiple myeloma.

The findings were published today in the medical journal Blood, and were presented at an international meeting of bone biology experts in Brisbane earlier this month.

The researchers tested a new type of treatment that specifically targets a protein called sclerostin, which in healthy bones is an important regulator of bone formation. Sclerostin halts bone formation, and the researchers speculated that if they could inhibit the action of sclerostin, they could reverse the devastating bone disease that occurs with multiple myeloma.

Dr Michelle McDonald and Professor Peter Croucher, of the Bone Biology Division of the Garvan Institute of Medical Research in Sydney, led the study.

“Multiple myeloma is a cancer that grows in bone, and in most patients it is associated with widespread bone loss, and recurrent bone fractures, which can be extremely painful and debilitating,” says Dr McDonald.

“The current treatment for myeloma-associated bone disease with bisphosphonate drugs prevents further bone loss, but it doesn’t fix damaged bones, so patients continue to fracture. We wanted to re-stimulate bone formation, and increase bone strength and resistance to fracture.”

The new therapeutic approach is an antibody that targets and neutralises sclerostin, and in previous clinical studies of osteoporosis, such antibodies have been shown to increase bone mass and reduce fracture incidence in patients.

The researchers tested the anti-sclerostin antibody in mouse models of multiple myeloma, and found that not only did it prevent further bone loss, it doubled bone volume in some of the mice.

Dr McDonald says, “When we looked at the bones before and after treatment, the difference was remarkable – we saw less lesions or ‘holes’ in the bones after anti-sclerostin treatment.

“These lesions are the primary cause of bone pain, so this is an extremely important result.”

The researchers have a biomechanical method to test bone strength and resistance to fracture, and found that the treatment also made the bones substantially stronger, with more than double the resistance to fracture observed in many of the tests.

They then combined the new antibody with zoledronic acid, a type of bisphosphonate drug, the current standard therapy for myeloma bone disease.

“Bisphosphonates work by preventing bone breakdown, so we combined zoledronic acid with the new anti-sclerostin antibody, that re-builds bone. Together, the impact on bone thickness, strength and resistance to fracture was greater than either treatment alone,” says Dr McDonald.

The findings provide a potential new clinical strategy for myeloma. While this disease is relatively rare, with approximately 1700 Australians diagnosed every year, the prognosis is extremely poor, with less than half of those diagnosed expected to survive for more than five years.

Prof Croucher, Head of the Bone Biology Division at Garvan, says that preventing the devastating bone disease of myeloma is critical to improve the prognosis for these people.

“Importantly, myelomas, like other cancers, vary from individual to individual and can therefore be difficult to target. By targeting sclerostin, we are blocking a protein that is active in every person’s bones, and not something unique to a person’s cancer. Therefore, in the future, when we test this antibody in humans, we are hopeful to see a response in most, if not all, patients,” Prof Croucher says.

“We are now looking towards clinical trials for this antibody, and in the future, development of this type of therapy for the clinical treatment of multiple myeloma.

“This therapeutic approach has the potential to transform the prognosis for myeloma patients, enhancing quality of life, and ultimately reducing mortality.

“It also has clinical implications for the treatment of other cancers that develop in the skeleton.”

Study Shows How an Opportunistic Microbe Kills Cancer Cells and Identifies Specialized Vesicles Responsible for Cell Reproduction

New study results show for the first time how dying cells ensure that they will be replaced, and suggests an ingenious, related new approach to shrinking cancerous tumors. A research team from Rush University Medical Center will publish a new paper this week in the journal Developmental Cell that describes two groundbreaking discoveries.

“I believe this discovery is going to have important ramifications on cancer biology and cancer drug development, and on the treatment of other diseases such as diabetic foot ulcers,” says Sasha Shafikhani, PhD, associate professor of Hematology, Oncology and Cell Therapy at Rush Medical College, who headed up the study.

The team made its two-pronged discovery while investigating how an opportunistic microbe kills cancer cells. For years, Shafikhani’s lab has been studying Pseudomonas aeruginosa, a bacterium that can be lethal, but only to people who are already wounded or sick. This pathogenic bacterium secretes several toxins that allow it to cause infection. One such toxins, ExoT, inhibits cell division and can severely impede wound healing, but it’s also known to kill cancer cells.

The researchers were trying to figure out ExoT’s lethal mechanisms against cancer when they unlocked, almost by accident, a mystery researchers have been trying to solve for years, Shafikhani says. For at least 20 years, medical researchers have wondered how cells, before they die in the normal process of apoptosis, manage to alert their neighbors of the need to replace them and compensate for their demise, so to ensure the organism’s survival. While shining a light on the lethal habits of Pseudomonas aeruginosa, Shafikhani’s team discovered what actually happens in that “compensatory proliferation signaling” (CPS) process.

For the first time, the investigators saw — and have shown in amazing videos they produced — that during CPS, dying cells release “microvesicles” containing the CrkI protein, which travel to neighboring cells and cause them, upon contact, to create new cells to replace the ones that are dying.

Apoptosis is part of life. “In the course of normal tissue turnover in humans, about one million cells die every second, through a highly-regulated process of apoptotic programmed cell death (PCD),” the new paper states. Apoptosis is not the only type of cell death, and not all cells dying of apoptosis are capable of CPS.

Not only that, but Shafikhani and his colleagues have demonstrated that if they knocked out the CrkI protein during CPS, either genetically or with the ExoT toxin, they could stop cell compensatory proliferation cold. That’s a trick P. aeruginosa uses to take advantage of damaged tissues, but it has exciting possibilities for disease treatment as well.

Apoptosis is of particular interest to cancer researchers because majority of the current cancer drugs kill cancer cells by apoptosis.

However, CPS can dog apoptosis in cancer treatment. Yes, treated cancer cells can be induced to die, but before they do, they call on nearby cancer cells to replace them, so the drug loses its effectiveness and the tumor persists. But if the communication between the dying cancer cells and neighboring cancer cells is blocked, Shafikhani says, the hope is that the treated cancer cells would not be replaced when they die, and hopefully the tumor would disappear.

“If it’s possible to uncouple CPS from apoptosis, we can develop new drugs that would improve the effectiveness of treatments already in use,” Shafikhani says.

In cancer cells, the CPS process and communication would need to be interrupted to prevent the development of new cancer cells; but in other conditions, the CPS process could be enhanced to accelerate the healing process. One of the possible long-term benefits of the discoveries set out in the new Developmental Cell article could be to use of these vesicles to encourage cell proliferation — in diabetic wounds where healing is not going well because tissue cells are dysfunctional and have reduced ability to regenerate, for example, Shafikhani says.

All the researchers on the new study were from Rush University Medical Center.

Cardiac stem cells from heart disease patients may be harmful

Patients with severe and end-stage heart failure have few treatment options available to them apart from transplants and “miraculous” stem cell therapy. But a new Tel Aviv University study finds that stem cell therapy may, in fact, harm heart disease patients.

The research, led by Prof. Jonathan Leor of TAU’s Sackler Faculty of Medicine and Sheba Medical Center and conducted by TAU’s Dr. Nili Naftali-Shani, explores the current practice of using cells from the host patient to repair tissue — and contends that this can prove deleterious or toxic for patients. The study was recently published in the journal Circulation.

“We found that, contrary to popular belief, tissue stem cells derived from sick hearts do not contribute to heart healing after injury,” said Prof. Leor. “Furthermore, we found that these cells are affected by the inflammatory environment and develop inflammatory properties. The affected stem cells may even exacerbate damage to the already diseased heart muscle.”

Tissue or adult stem cells — “blank” cells that can act as a repair kit for the body by replacing damaged tissue — encourage the regeneration of blood vessel cells and new heart muscle tissue. Faced with a worse survival rate than many cancers, many heart failure patients have turned to stem cell therapy as a last resort.

“But our findings suggest that stem cells, like any drug, can have adverse effects,” said Prof. Leor. “We concluded that stem cells used in cardiac therapy should be drawn from healthy donors or be better genetically engineered for the patient.”

Hope for improved cardiac stem cell therapy

In addition, the researchers also discovered the molecular pathway involved in the negative interaction between stem cells and the immune system as they isolated stem cells in mouse models of heart disease. After exploring the molecular pathway in mice, the researchers focused on cardiac stem cells in patients with heart disease.

The results could help improve the use of autologous stem cells — those drawn from the patients themselves — in cardiac therapy, Prof. Leor said.

“We showed that the deletion of the gene responsible for this pathway can restore the original therapeutic function of the cells,” said Prof. Leor. “Our findings determine the potential negative effects of inflammation on stem cell function as they’re currently used. The use of autologous stem cells from patients with heart disease should be modified. Only stem cells from healthy donors or genetically engineered cells should be used in treating cardiac conditions.”

The researchers are currently testing a gene editing technique (CRISPER) to inhibit the gene responsible for the negative inflammatory properties of the cardiac stem cells of heart disease patients. “We hope our engineered stem cells will be resistant to the negative effects of the immune system,” said Prof. Leor.

First-In-Human Clinical Trial Aims to Extend Remission for Children and Young Adults With Leukemia Treated With T-Cell Immunotherapy

Phase 1 pilot study utilizes T-cell antigen presenting cells to prolong the persistence of cancer-fighting chimeric antigen receptor (CAR) T cells, reduce the relapse rate

After phase 1 results of Seattle Children’s Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting  93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient’s chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer.

The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells.

“While it’s promising that we’re able to get these patients who are very sick back into remission, we’re also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return,” said Dr. Colleen Annesley, an oncologist at Seattle Children’s and the lead investigator of the PLAT-03 trial. “We’re pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission.”

In the PLAT-03 trial, patients will receive “booster” infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission.

PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children’s PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them.

The PLAT-03 trial is one of several trials that Seattle Children’s researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers.

“We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients,” said Dr. Rebecca Gardner, Seattle Children’s oncologist and the lead investigator of the PLAT-02 trial. “We’re also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks.”

To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children’s On the Pulse blog.

The T-cell immunotherapy trials at Seattle Children’s are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer’s donation page.

For more information on immunotherapy research trials at Seattle Children’s, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org.

For Women at Risk of Hereditary Breast Cancer, Multigene Test Could Help Extend Life Expectancy

Value in Health, the official journal of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), announced today the publication of new research indicating that testing for variants in 7 cancer-associated genes (versus the usual process of testing in just 2 genes) followed by risk-reduction management could cost-effectively improve life expectancy for women at risk of hereditary breast cancer. The report of these findings, A Multigene Test Could Cost-Effectively Help Extend Life Expectancy for Women at Risk of Hereditary Breast Cancer, was published in the April 2017 issue.

Using hypothetical cohorts of women at risk of hereditary breast cancer, the authors used a decision-analytic model to compare the relative cost and effectiveness of two test strategies for detecting pathogenic genetic variants: 1) the usual BRCA1/2 test strategy, and 2) a next-generation 7-gene strategy that tests for variants not only in BRCA1 and BRCA2, but also in TP53, PTEN, CDH1, STK11, and PALB2. The authors then used these test results to select appropriate breast cancer risk reduction treatments / therapies.

In the base-case scenario for 50- and 40-year-old women undergoing genetic testing, the incremental cost-effectiveness ratio (ICER) for the 7-gene test strategy compared with the BRCA1/2 test strategy was $42,067 and $23,734 per life-year gained, or $69,920 and $48,328 per quality-adjusted life-year gained, respectively. At these ICER levels, the 7-gene test strategy would be considered cost effective according to the World Health Organization guidelines.

“Pathogenic variants in the BRCA1 and BRCA2 genes explain only about 15% of the breast cancer familial relative risk,” said lead author Yonghong Li, PhD, Quest Diagnostics, USA, “while pathogenic variants in other genes, including TP53, PTEN, CDH1, and PALB2 contribute further to the familial relative risk. The results of this study,” Dr. Li added, “demonstrate the potential value of newer testing options that allow for the simultaneous analysis of expanded panels of additional genes whose pathogenic variants confer moderate to high risk for breast cancer.”

Success of Sensory Cell Regeneration Raises Hope for Hearing Restoration

In an apparent first, St. Jude Children’s Research Hospital investigators have used genetic manipulation to regenerate auditory hair cells in adult mice. The research marks a possible advance in treatment of hearing loss in humans. The study appears today in the journal Cell Reports.

Loss of auditory hair cells due to prolonged exposure to loud noise, accidents, illness, aging or medication is a leading cause of hearing loss and long-term disability in adults worldwide. Some childhood cancer survivors are also at risk because of hair cells damage due to certain chemotherapy agents. Treatment has focused on electronic devices like hearing aids or cochlear implants because once lost, human auditory hair cells do not grow back.

“In this study, we looked to Mother Nature for answers and we were rewarded,” said corresponding author Jian Zuo, Ph.D., a member of the St. Jude Department of Developmental Neurobiology. “Unlike in humans, auditory hair cells do regenerate in fish and chicken. The process involves down-regulating expression of the protein p27 and up-regulating the expression of the protein Atoh1. So we tried the same approach in specially bred mice.”

By manipulating the same genes, Zuo and his colleagues induced supporting cells located in the inner ear of adult mice to take on the appearance of immature hair cells and to begin producing some of the signature proteins of hair cells.

The scientists also identified a genetic pathway for hair cell regeneration and detailed how proteins in that pathway cooperate to foster the process. The pathway includes the proteins GATA3 and POU4F3 along with p27 and ATOH1. In fact, investigators found that POU4F3 alone was sufficient to regenerate hair cells, but that more hair cells were regenerated when both ATOH1 and POU4F3 were involved.

“Work in other organs has shown that reprogramming cells is rarely accomplished by manipulating a single factor,” Zuo said. “This study suggests that supporting cells in the cochlea are no exception and may benefit from therapies that target the proteins identified in this study.”

The findings have implications for a phase 1 clinical trial now underway that uses gene therapy to restart expression of ATOH1 to regenerate hair cells for treatment of hearing loss.

ATOH1 is a transcription factor necessary for hair cell development. In humans and other mammals, the gene is switched off when the process is complete. In humans, ATOH1 production ceases before birth.

“This study suggests that targeting p27, GATA3 and POU4F3 may enhance the outcome of gene therapy and other approaches that aim to restart ATOH1 expression,” Zuo said.

The research also revealed a novel role for p27. The protein is best known as serving as a check on cell proliferation. However, in this study p27 suppressed GATA3 production. Since GATA3 and ATOH1 work together to increase expression of POU4F3, reducing GATA3 levels also reduced expression of POU4F3. When the p27 gene was deleted in mice, GATA3 levels increased along with expression of POU4F3. Hair cell regeneration increased as well.

“Work continues to identify the other factors, including small molecules, necessary to not only promote the maturation and survival of the newly generated hair cells, but also increase their number,” Zuo said.

Rare Type of Immune Cell Responsible for Progression of Heart Inflammation to Heart Failure in Mice

A new study in mice reveals that eosinophils, a type of disease-fighting white blood cell, appear to be at least partly responsible for the progression of heart muscle inflammation to heart failure in mice.

In a report on the findings, published in The Journal of Experimental Medicine on March 16, researchers found that while eosinophils are not required for heart inflammation to occur, they are needed for it to progress to a condition known as inflammatory dilated cardiomyopathy (DCMi) in mice. The discovery, they say, advances information about the impact of eosinophils on heart function.

“Other studies have shown that people with high levels of eosinophils develop a number of heart diseases. This new work has provided more details about how these immune system cells may lead to deterioration of heart muscle function in mice in a way that lets us draw some parallels to human disease processes,” says Daniela Cihakova, M.D., Ph.D., associate professor of pathology at the Johns Hopkins University School of Medicine and the paper’s senior author.

Heart inflammation, or myocarditis, is rarely diagnosed because it doesn’t always cause severe symptoms and it requires a biopsy to be taken from the patient’s heart. This makes it difficult to study the outcomes of the disease. “We don’t understand why the hearts of some people will heal while those of others develop chronic disease,” says Cihakova.

Different types of myocarditis are distinguished based on the type of immune cell that predominates the inflammation of the heart. For example, in eosinophilic myocarditis, numerous eosinophils infiltrate the heart. It is not known if some types of myocarditis are more likely to progress to DCMi than others. “Our studies show that the presence of eosinophils in the heart makes mice more likely to get DCMi following myocarditis. And if there are a lot of eosinophils, the mice develop even more severe heart failure,” says Nicola Diny, a Ph.D. student in the Bloomberg School of Public Health and the study’s first author. “It will be important to test if the same is true in patients. That way, we may be able to intervene early and prevent DCMi.”

This study, says Cihakova, is the first to examine the role eosinophils play in the development and severity of heart inflammation, and the subsequent progression of inflammation to DCMi. The study addresses a National Institutes of Health-identified need for preclinical models and a clearer understanding of how eosinophils drive heart damage.

For the study, Cihakova and her team first induced myocarditis in two groups of mice: normal mice and a group of mice genetically modified to be eosinophil-deficient. Myocarditis was induced through a process called experimental autoimmune myocarditis, in which mice are immunized with a peptide from heart muscle cells to initiate an immune response against the heart. After 21 days, the researchers found similar levels of acute inflammation in the hearts of both groups by studying the hearts’ tissue. But when the team checked the mice’s hearts later on for evidence of heart failure, the differences between the eosinophil-deficient and the normal mice were striking. The normal mice developed heart failure, while the eosinophil-deficient mice showed no signs of reduced heart function.

“These surprising results told us that it is not the overall severity of inflammation but rather the types of immune cells in the heart that decide whether myocarditis develops into heart failure,” says Diny.

The researchers also examined the hearts for fibrosis, or scar tissue, which develops when mammalian (including human) heart muscles die. This type of scar tissue is also found in DCMi. Although both groups of mice had similar degrees of scar tissue, the eosinophil-deficient mice’s heart functions weren’t negatively affected, while the normal mice developed DCMi.

“This told us that in the absence of eosinophils, heart function can be preserved despite scar tissue formation,” Cihakova says. “It’s also important to note that although eosinophils accounted for just 1 to 3 percent of all heart-infiltrating cells in normal mice, this small percentage can still drive heart failure.”

In another set of experiments, the research team used genetically modified mice, called IL5Tg mice, which have an excess of the protein IL5 that causes the body to make eosinophils. The IL5Tg mice had more inflammation in the atria, or upper chambers of the heart, compared to normal mice in the acute stage and more atrial scar tissue in the chronic stage. IL5Tg mice also had more heart-infiltrating cells in general. Eosinophils accounted for more than 60 percent of heart-infiltrating cells in the IL5Tg mice’s hearts, compared to only 3 percent in normal mice. When the team examined the heart function some 45 days after the start of the experiment, the IL5Tg mice had developed severe DCMi.

To examine whether humans with eosinophil-driven myocarditis also developed inflammation in the atria, the researchers obtained heart tissue samples and cardiac MRI scans from three patients seen at The Johns Hopkins Hospital, all of whom had confirmed eosinophil-driven inflammation.

The images showed that two patients had either inflammation or scar tissue in the atria, which suggests that atrial inflammation and/or scar tissue may also be a feature in humans with eosinophil-driven inflammation, Cihakova says.

To determine whether the IL5 protein is necessary for DCMi development, the research team next examined IL5-deficient mice. The scientists found that they had both inflammation and DCMi severity similar to that of normal mice, suggesting that the IL5 protein is not necessary for DCMi to develop.

Finally, to confirm the differences between the effects of IL5 and eosinophils, the team bred the eosinophil-deficient mice to have excess IL5. Compared to normal mice, these mice showed no decrease in heart function and appeared completely protected from DCMi, which confirms that it is the eosinophils themselves, not high levels of IL5, that are responsible for DCMi development, the investigators say.

To learn more about how eosinophils might drive DCMi progression, the investigators built on the knowledge that eosinophils harbor granules, some of which can kill cells, while others change the function of cells.

“We didn’t see any differences in cell death between the normal mice and those with or without too many eosinophils, so we became interested in the molecules that can change the function of other cells,” says Diny.

In particular, one protein, called IL4, caught the researchers’ attention. Other studies had shown that IL4 made by eosinophils has diverse functions in liver repair and fat tissue. “We wondered if this protein from eosinophils may also be important in the heart,” Cihakova says.

First, the research team used a mouse in which cells that make IL4 turned fluorescent green, thereby allowing researchers to tell where IL4 is made. The team found that eosinophils accounted for the majority of IL4-producing cells. When they used mice that lacked IL4 in all cells, these mice were completely protected from DCMi, just like the eosinophil-deficient mice.

Finally, to determine whether IL4 specifically from eosinophils is necessary for DCMi development, the team used genetically modified mice with no IL4 in their eosinophils but with IL4 in other heart-infiltrating cells. These mice developed less severe DCMi compared to normal mice, which confirms that eosinophils are responsible for DCMi development through IL4.

“The take-home message is that inflammation severity doesn’t necessarily determine long-term disease progression, but specific infiltrating cell types — eosinophils, in this case — do,” says Cihakova. Because eosinophil-driven inflammation is so clinically rare, the percentage of people who develop DCMi is unknown, she notes.

While no drugs are currently available to stop or delay the development of DCMi, the researchers hope their findings will help establish a novel target for IL4-blocking medicines that might be used to treat people with myocarditis, possibly preventing disease progression and the need for heart transplantation.

16 Aplastic Anemia Patients Free Of Disease After Bone Marrow Transplant and Chemo

Physicians at the Johns Hopkins Kimmel Cancer Center report they have successfully treated 16 patients with a rare and lethal form of bone marrow failure called severe aplastic anemia using partially matched bone marrow transplants followed by two high doses of a common chemotherapy drug. In a report on the new transplant-chemo regimen, published online Dec. 22, 2016, in Biology of Blood and Marrow Transplantation, the Johns Hopkins team says that more than a year after their transplants, all of the patients have stopped taking immunosuppressive drugs commonly used to treat the disorder and have no evidence of the disease.

“Our findings have the potential to greatly widen treatment options for the vast majority of severe aplastic anemia patients,” according to Robert Brodsky, M.D., professor of medicine and oncology at the Johns Hopkins Kimmel Cancer Center and an author of the report.

Results of the small clinical trial have already prompted the organization of a larger national trial being led by Amy DeZern, M.D., an assistant professor of oncology and medicine at the Johns Hopkins Kimmel Cancer Center, with plans to involve patients at 25 medical centers across the country.

Diagnosed in about one in 250,000 people each year, aplastic anemia occurs when one’s own immune system damages blood-making bone marrow cells, which gradually stop producing red and white blood cells and platelets.

Patients must receive frequent blood transfusions, take multiple medicines to suppress the autoimmune response that damages the marrow, take other drugs to prevent infections, and limit contact with the outside world to avoid infection and even minor injury. Over the long term, most patients eventually die of infections.

When immunosuppressive therapy fails to keep the disease in check — in as many as 30 to 40 percent of patients — doctors usually prescribe a drug called eltrombopag, which is used in a variety of blood disorders to increase platelets. The drug, according to the Johns Hopkins experts, works only in about 30 percent of patients and usually leads to a partial, not complete, response.

Brodsky and DeZern say that the only curative treatment is a bone marrow transplant, but few patients have donors who are “fully matched” — sharing the same collection of immune-stimulating proteins that decorate every cell in the body.

In an effort to overcome the donor shortage and offer transplant to more patients, DeZern, Brodsky and their colleagues enrolled 16 patients between 11 and 69 years of age in this study from July 2011 through August 2016.

Each of the patients had failed to respond to immunosuppressive therapy or other drug treatments. None had access to a related fully matched bone marrow donor but did have an available and willing donor who was a half match. Three patients used unrelated donors.

After administering a cocktail of drugs designed to suppress their immune system and prevent rejection of the donor marrow, the patients received half-matched bone marrow transplants, some from siblings or parents, and others from unrelated donors.

Three and four days after their transplants, the patients received high doses of the chemotherapy drug cyclophosphamide. For the next year, or slightly longer, they remained on immunosuppressive medications, including tacrolimus, then stopped taking them.

Within weeks of their transplants, tests showed that each of the patients’ red and white blood cell and platelet counts had returned to normal levels without the need for blood transfusions. Once immunosuppressive therapy was stopped, none of the patients required further treatment related to their disease, the Johns Hopkins team reported.

Although 13 patients were able to discontinue immunosuppressive drugs a year after their transplant, three developed mild graft-versus-host disease (GVHD), a common complication of bone marrow transplants that occurs when immune cells in the transplant attack the newly transplanted cells. Two patients had mild GVHD that appeared on their skin, and one patient’s GVHD occurred in the mouth and skin. After a few extra months of immunosuppressive therapy, their GVHD subsided, and they also were able to stop taking these medications.

Ending all therapy related to their disease has been life-changing for the patients, says DeZern. “It’s like night and day,” she says. “They go from not knowing if they have a future to hoping for what they’d hoped for before they got sick. It’s that transformative.”

Successful transplants using partial match donors, Brodsky says, open up the transplant option to nearly all patients with this condition, especially minority patients. Seven of the 16 patients treated at Johns Hopkins self-identified as nonwhite.

A full sibling only has a 25 percent chance of being a full match. However, 100 percent of parents and 50 percent of siblings or half-siblings are half matches, regardless of ethnicity. The average person in the United States has about four half matches or better. “Now, a therapy that used to be available to 25 to 30 percent of patients with severe aplastic anemia is potentially available to more than 95 percent,” says Brodsky.

The idea of using cyclophosphamide after a partial-match transplant was first pioneered decades ago by Johns Hopkins Kimmel Cancer Center experts. Brodsky says the drug destroys patient’s diseased immune system cells but does not harm the donor’s blood stem cells, which create new disease-free blood cells in the patient.

Bone marrow transplants are costly — sometimes exceeding more than $300,000. However, Brodsky and DeZern say that full and half-matched transplants are life-saving for many, and there is cost-saving potential when aplastic anemia patients can avoid a lifetime of immunosuppressive therapy, hospitalizations, medications and blood transfusions.

TapImmune’s T-Cell Cancer Vaccine for Worldwide Eradication of Women’s Cancers

Early proof of efficacy, scalability with cost effective manufacturing, and testability in large Phase III FDA trials are the reasons why TapImmune (TPIV) is the leading T-cell cancer vaccine company and will dominate this space. World class collaborators including the Mayo Clinic, AstraZeneca (AZN), Sloan Kettering and Phase II trial funding from the U.S. Department of Defense prove this point.

Vaccines have eradicated numerous infectious diseases. Cancer is vaccine’s next target, powered by T-cells. White blood cells that are responsible for detecting foreign or abnormal cells including cancerous ones, T-cells specialize in seeking, attaching to, and destroying cancer cells with the help of the rest of the immune system.

Cunning cancer cells often find ways to con the immune system though, making them invisible to T-cells. TapImmune’s effective T-cell cancer vaccine activates cytotoxic T cells and directs them to see and attack specific types of cancer.  TapImmune’s vaccines are superior to other T-cell based cancer treatment candidates due to their powerful and unique combination of proprietary peptide antigens.

Stimulating both killer T-cells (CD8) and helper T-cells (CD4) creates sustained and long lasting tumor cell killing.  Roche’s (ROG:VS) Herceptin, a monoclonal antibody isn’t even designed to kill tumor cells, but in a market desperate for a solution, it has become standard of care by merely slowing down tumor growth. 2015 Herceptin sales exceeded $6.6 billion. If slowing down cancer makes Herceptin a blockbuster, then TapImmune’s cancer killing T-cell vaccine should become an uber-blockbuster and command sales far higher than Herceptin.

Early efficacy results in Phase I trials conducted at the prestigious Mayo Clinic show immune response to TapImmune’s T-cell vaccine in between 75% and 100% of patients treated. These impressive data were published in the Journal of Clinical Oncology and presented at oncology’s top scientific conference, ASCO, as well as at the San Antonio Breast Cancer Symposium.

Beyond efficacy, off-the-shelf platform technology is what sets TapImmune apart in the market and gives its T-cell cancer vaccines the dominant position.

While other cancer vaccines have shown promise, they have for the most part been autologous – meaning doctors take tumor cells from a specific person, process those cells into a vaccine, and reinsert this one-person-specific vaccine into that same person. This kind of personalized medicine is very expensive and difficult to run through large Phase III studies given the way FDA trials are conducted today.

TapImmune’s T-cell vaccines have been specifically designed for high efficacy, high scalability, cost effectiveness, and are ideally suited for large scale FDA testing. This makes them more likely to get FDA approved and reimbursed once on the market.

Today, TapImmune is testing its lead cancer vaccine TPIV-200 in two Phase II studies and is set to begin enrollment any day in two more Phase II studies. Should any of these four trials show promise, TapImmune will charge into larger scale Phase IIIs, armed with an off-the-shelf, consistently manufactured, low cost cancer vaccine that can be used as a therapeutic and prophylactic (preventative).

Indications are ovarian cancer and triple negative breast cancer, two of the hardest women’s cancers to treat. The breast cancer treatment market will top $20 billion by 2024 and ovarian cancer will be $1.4 billion by 2021 according to Decision Resources.

Instead of creating a specific vaccine for each person, TapImmune has selected excellent cancer targets including folate receptor alpha and HER2/neu, which are expressed on the surface of majority of tumor target cells. Deploying TapImmune’s proprietary antigen expression system, these antigens were selected from immune responses in patients to broadly stimulate T-helper cells, T-killer cells and T-memory cells.

Blockbuster Herceptin can only be used in 15-20% of the HER2/neu positive breast cancer population. Besting this by far, TapImmune’s T-cell cancer vaccine is applicable to over 50% of the HER2/neu patient population.

TapImmune vaccines cover about 85% of genotypes, offering broad population coverage from one easy to manufacture vaccine. With this effective formula, TapImmune can mass manufacture cancer vaccines that can be used on any person who needs it. No custom tailoring needed here.

HER2/neu is a valuable cancer target for both ovarian and colorectal cancer, both diseases where there are very few therapeutic options. In breast cancer as well, HER2/neu is overexpressed in ~ 30% of patients.

An equally powerful target is folate receptor alpha, overexpressed in 90% of ovarian cancer cells, over 80% of triple negative breast cancer, and 80% non-small cell lung cancer patients. In the US, approximately 30,000 ovarian cancer and 40,000 triple negative breast cancer patients are newly diagnosed every year. The only treatment options for these patients are surgery, radiation and chemotherapy. With time to recurrence being relatively short, survival prognosis is extremely poor after recurrence.

Fast Track and Orphan Drug designations have been granted by the U.S. FDA to TapImmune’s TPIV 200 in the treatment of ovarian cancer. There is every reason in the world for Fast Track to also be granted for a cancer vaccine to prevent recurrence in the breast cancer population.

Big pharma and the world’s leading medical institutions have independently vetted TapImmune’s technology.

A joint AstraZeneca-TapImmune Phase II ovarian cancer trial is now enrolling patients at the prestigious Sloan Kettering Institute. The trial is testing a combination therapy – TapImmune’s TPIV 200 and AstraZeneca’s durvalumab an anti-PD-L1 antibody, in 40 women who have high-grade ovarian cancer and have not been responsive to platinum chemotherapy, currently the standard of care for advanced ovarian cancer.

Synthetic Stem Cells Could Offer Therapeutic Benefits, Reduced Risks

Researchers from North Carolina State University, the University of North Carolina at Chapel Hill and First Affiliated Hospital of Zhengzhou University have developed a synthetic version of a cardiac stem cell. These synthetic stem cells offer therapeutic benefits comparable to those from natural stem cells and could reduce some of the risks associated with stem cell therapies. Additionally, these cells have better preservation stability and the technology is generalizable to other types of stem cells.

Stem cell therapies work by promoting endogenous repair; that is, they aid damaged tissue in repairing itself by secreting “paracrine factors,” including proteins and genetic materials. While stem cell therapies can be effective, they are also associated with some risks of both tumor growth and immune rejection. Also, the cells themselves are very fragile, requiring careful storage and a multi-step process of typing and characterization before they can be used.

Ke Cheng, associate professor of molecular biomedical sciences at NC State University, associate professor in the joint biomedical engineering program at NC State and UNC and adjunct associate professor at the UNC Eshelman School of Pharmacy, led a team in developing the synthetic version of a cardiac stem cell that could be used in off-the-shelf applications.

Cheng and his colleagues fabricated a cell-mimicking microparticle (CMMP) from poly (lactic-co-glycolic acid) or PLGA, a biodegradable and biocompatible polymer. The researchers then harvested growth factor proteins from cultured human cardiac stem cells and added them to the PLGA. Finally, they coated the particle with cardiac stem cell membrane.

“We took the cargo and the shell of the stem cell and packaged it into a biodegradable particle,” Cheng says.

When tested in vitro, both the CMMP and cardiac stem cell promoted the growth of cardiac muscle cells. They also tested the CMMP in a mouse model with myocardial infarction, and found that its ability to bind to cardiac tissue and promote growth after a heart attack was comparable to that of cardiac stem cells. Due to its structure, CMMP cannot replicate – reducing the risk of tumor formation.

“The synthetic cells operate much the same way a deactivated vaccine works,” Cheng says. “Their membranes allow them to bypass the immune response, bind to cardiac tissue, release the growth factors and generate repair, but they cannot amplify by themselves. So you get the benefits of stem cell therapy without risks.”

The synthetic stem cells are much more durable than human stem cells, and can tolerate harsh freezing and thawing. They also don’t have to be derived from the patient’s own cells. And the manufacturing process can be used with any type of stem cell.

“We are hoping that this may be a first step toward a truly off-the-shelf stem cell product that would enable people to receive beneficial stem cell therapies when they’re needed, without costly delays,” Cheng says.

New stem cell delivery approach regenerates dental pulp-like tissue in a rodent model

When a tooth is damaged, either by severe decay or trauma, the living tissues that comprise the sensitive inner dental pulp become exposed and vulnerable to harmful bacteria. Once infection takes hold, few treatment options–primarily root canals or tooth extraction–are available to alleviate the painful symptoms.

Researchers at Tufts University School of Dental Medicine (TUSDM) now show that using a collagen-based biomaterial to deliver stem cells inside damaged teeth can regenerate dental pulp-like tissues in animal model experiments. The study, published online in the Journal of Dental Research on Dec. 15, supports the potential of this approach as part of a strategy for restoring natural tooth functionality.

“Endodontic treatment, such as a root canal, essentially kills a once living tooth. It dries out over time, becomes brittle and can crack, and eventually might have to be replaced with a prosthesis,” said senior study author Pamela Yelick, PhD, professor at TUSDM and director of its Division of Craniofacial and Molecular Genetics. “Our findings validate the potential of an alternative approach to endodontic treatment, with the goal of regenerating a damaged tooth so that it remains living and functions like any other normal tooth.”

Yelick and her colleagues, including lead study author Arwa Khayat, former graduate student in dental research at TUSDM, examined the safety and efficacy of gelatin methacrylate (GelMA)–a low-cost hydrogel derived from naturally occurring collagen–as a scaffold to support the growth of new dental pulp tissue. Using GelMA, the team encapsulated a mix of human dental pulp stem cells–obtained from extracted wisdom teeth–and endothelial cells, which accelerate cell growth. This mix was delivered into isolated, previously damaged human tooth roots, which were extracted from patients as part of unrelated clinical treatment and sterilized of remaining living tissue. The roots were then implanted and allowed to grow in a rodent animal model for up to eight weeks.

The researchers observed pulp-like tissue inside the once empty tooth roots after two weeks. Increased cell growth and the formation of blood vessels occurred after four weeks. At the eight-week mark, pulp-like tissue filled the entire dental pulp space, complete with highly organized blood vessels populated with red blood cells. The team also observed the formation of cellular extensions and strong adhesion into dentin–the hard, bony tissue that forms the bulk of a tooth. The team saw no inflammation at the site of implantation, and found no inflammatory cells inside implanted tooth roots, which verified the biocompatibility of GelMA.

Control experiments, which involved empty tooth roots or tooth roots with only GelMA and no encapsulated cells, showed significantly less growth, unorganized blood vessel formation, and poor or nonexistent dentin attachment.

The results support GelMA-encapsulated human dental stem cells and umbilical vein endothelial cells as part of a promising strategy to restore normal tooth function, according to the study authors. However, they note that the current study was limited to partial tooth roots and did not examine nerve formation in regenerated dental pulp tissue. They emphasize the need for additional safety and efficacy studies in larger animal models before human clinical trials can be considered.

“A significant amount of work remains to be done, but if we can extend and validate our findings in additional experimental models, this approach could become a clinically relevant therapy in the future,” said Yelick, who is also a member of the Cell, Molecular & Developmental Biology; Genetics; and Pharmacology & Experimental Therapeutics programs at the Sackler School of Graduate Biomedical Sciences at Tufts. “Our work is early stage, but we are excited for the possibility of someday giving patients the option of regenerating their own teeth.” Continue reading “New stem cell delivery approach regenerates dental pulp-like tissue in a rodent model”

Leading Cell Therapy Company Pluristem to Partner with Japan’s Sosei for Commercialization of Regenerative Medicines in Japan

In a major global regenerative medicine deal, Israel-based Pluristem Therapeutics and Japan’s Sosei CVC, the venture capital arm of Japanese biopharma company Sosei Group, agreed to form a joint venture (JV) to commercialize Pluristem’s PLX-PAD cells in Japan. The deal marks Pluristem’s commercial entry into Japan and expands Sosei’s pipeline into regenerative medicines.

Pluristem has been active in the Japan market through discussions with, and applications to, Japan’s health regulatory agency, Pharmaceuticals and Medical Devices Agency (PMDA), seeking accelerated approval pathways for its PLX-PAD cells. The successful result is the PDMA’s acceptance of PLX-PAD cells into the accelerated pathways for regenerative medicine, making possible regulatory approval of PLX-PAD cells in the treatment of Critical Limb Ischemia (CLI) following just one 75-person clinical trial. This JV deal in Japan confirms Pluristem’s strategy of pursuing early approval pathways, as they also achieved in Europe.

Per the terms of the agreement between the two companies, an $11 million investment will be made by Sosei into the JV to fund a clinical trial of PLX-PAD for CLI that may directly lead to early conditional marketing approval and reimbursement based the PMDA’s accelerated regulatory pathway for regenerative medicine.  Pluristem gets 35% of the JV and its future profits. All proprietary rights related to PLX-PAD will be exclusively owned by Pluristem.

Sosei was likely compelled to partner with Pluristem based on the company’s advanced stem cell technology and its regulatory advantages in Japan. In addition to this JV with Pluristem, Sosei has partnerships with Novartis, AstraZeneca, MedIumme, and others. Pluristem and Sosei plan to enter into a definitive agreement no later than March 31, 2017.

The American Society of Nephrology (ASN) Applauds Congress and President Barack H. Obama for Passage and Signing into Law the 21st Century Cures Act

The American Society of Nephrology (ASN) applauds Congress and President Barack H. Obama for passage and signing into law the 21st Century Cures Act today. ASN advocated for specific provisions of the new law to benefit the more than 20 million Americans afflicted with kidney diseases and the 650,000 with kidney failure who rely on a kidney transplant or dialysis to live.

“The 21st Century Cures Act takes dramatic new steps to encourage research and innovation that could benefit the millions of Americans suffering from chronic diseases, including kidney diseases,” said ASN President Raymond C. Harris, MD, FASN.
The new law calls on the National Institutes of Health (NIH) to support prize competitions to improve patients’ health in fields where there is a significant disease burden or that current investment is disproportionately small relative to federal expenditures on that condition. The Medicare program entitles every American suffering from kidney failure—regardless of age—to lifesaving dialysis at a cost of nearly $35 billion annually, more than NIH’s total budget.

“ASN is heartened by this commitment to using the power of prize competitions to foster innovation on behalf of the patients most in need. Last year, the society announced its pledge of the first $7 million dollars toward a prize competition to develop a novel wearable or implantable device that replaces kidney function and improves patient quality of life,” Harris said. “As ASN seeks a partner to launch the prize competition in 2017, I anticipate we will continue close dialogue with NIH and other federal agencies whose expertise and collaboration would be invaluable in making this important endeavor a success.”

ASN applauded the leadership of House Energy and Commerce Chair Fred Upton (R-MI-6th) and Representative Diane DeGette (D-CO-6th), who shepherded the legislation through the House and Senate HELP Committee Chair Lamar Alexander (R-TN) and Ranking Member Patty Murray (D-WA). “There would be no announcement today without their vision and tireless efforts,” Harris commented.

In addition to advocating for prize competitions, ASN encouraged other provisions, including:

1) Permitting patients with kidney failure to enroll in Medicare Advantage Previously, kidney failure was the only pre-existing condition preventing patients from enrolling in Medicare Advantage. This change creates patient choice to selecting a plan that best fits their needs.
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2) Using patient preferences in decision making by the Food and Drug Administration (FDA). The new law clarifies that patients’ own experiences will be incorporated into the FDA decision making for medical products.

3) Increasing funding for NIH research and innovation. The Act bolsters funding for research and innovation that lags behind the costs of caring for patients suffering from chronic diseases.