Novel Gene Therapy Provides Significant Wound Healing in Severe Form of Epidermolysis Bullosa

Recent data presented at the Society for Investigative Dermatology (SID) conference demonstrated that EB-101, a gene therapy provided significant wound healing in patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB), a severe form of epidermolysis bullosa (EB).

RDEB is a subtype of an inherited genetic skin disorder characterized by chronic skin blistering, open and painful wounds, joint contractures, esophageal strictures, pseudosyndactyly, corneal abrasions and a shortened life span. Patients with RDEB lack functional type VII collagen owing to mutations in the gene COL7A1 that encodes for C7 and is the main component of anchoring fibrils, which stabilize the dermal-epidermal basement membrane

EB-101 is an autologous, ex-vivo gene therapy in which COL7A1 is transduced into autologous keratinocytes for the treatment of Recessive Dystrophic Epidermolysis Bullosa (RDEB).

The therapy provided healing (defined as greater than 50% healed) in 100% of Treated Wounds (36/36) at 3 Months; 89% (32/36) at 6 months, 83% (20/24) at 12 months, 88% (21/24) at 24 Months and 100% (6/6) at 36 months Post-Administration. The findings were presented by Abeona Therapeutics’ a leading clinical-stage biopharmaceutical company focused on developing novel gene therapies for life-threatening rare diseases, and the scientific and clinical collaborators at Stanford University School of Medicine, a center of excellence for the treatment of patients with epidermolysis bullosa.

The company also unveiled updated clinical data from the ongoing Phase 1/2 clinical trial for the EB-101 gene therapy program for patients with, along with supportive natural history data for 128 patients with the fatal skin disease.

 “Last week at the SID conference, our EB-101 team of clinical investigators and scientific collaborators presented data from the ongoing Phase 1/2 gene therapy clinical trial and a supportive natural history study of patients with RDEB that highlight the unprecedented wound healing and durable collagen C7 expression of four patients through two years’ post-treatment, including one patient that has continued to see EB-101 treated wounds remain healed three years post-treatment. The relevance of these benefits is highlighted when compared to non-treated control wounds evaluated from the 128-patient natural history study, which showed that RBEB patients suffer chronic and recurrent wounds that do not heal on their own and persist for several years,” said Timothy J. Miller, Ph.D., President and CEO of Abeona Therapeutics.

In the Phase 1/2 trial, EB-101 was administered to non-healing chronic wounds [mean length of time wounds were unhealed (unclosed) was 8.5 years prior to the gene therapy administration] on each subject and assessed for wound healing at predefined time points over years. The primary endpoint of the clinical trial is to assess safety and evaluate wound closure after EB-101 administration compared to control untreated wounds. Secondary endpoints include expression of full-length collagen C7 and restoration of anchoring fibrils at three and six months’ post-administration.

As reflected at the conference by Stanford collaborators, wounds were evaluated at three, six, 12, 24 and 36 months for appearance, durability, and resistance to blistering**:

Wound healing >50%:  defined as >50% closure after EB-101 administration was observed in:
– 100% (36/36 treated wounds, n=6 subjects) at 3 months;
– 89% (32/36 treated wounds, n=6 subjects) at 6 months;
– 83% (20/24 treated wounds, n=4 subjects) at 12 months,
– 88% (21/24 treated wounds, n=4 subjects) at 24 months,
– 100% (6/6 treated wounds, n=1 subject) at 36 months post-administration.

Wound healing >75%: defined as >75% closure after EB-101 administration was observed in:
– 83% (30/36 treated wounds, n=6 subjects) at 3 months;
– 61% (22/36 treated wounds, n=6 subjects) at 6 months;
– 50% (12/24 treated wounds, n=4 subjects) at 12 months;
– 71% (17/24 treated wounds, n=4 subjects) at 24 months;
– 83% (5/6 treated wounds, n=1 subject) at 36 months post-administration.

Collagen VII (C7) expression observed: C7 and morphologically normal NC2 reactive anchoring fibrils – the “zipper” that holds skin onto the underlying tissue and the primary deficit in RDEB patients – have been observed in EB-101 treatments up to two years post administration.

Natural History Study

Data from a supportive natural history study of 1,436 wounds of 128 patients with RDEB, established by Stanford and EBCare Registry, were also presented at the conference. The natural history study characterized both chronic non-healing wounds, defined as an area that does not heal ≥12 weeks, and recurrent wounds, defined as an area that partially heals but then easily re-blisters. Results presented were characterized as 1041 recurrent wounds and 395 chronic open wounds.

Notably, in the natural history study, 13 RDEB patients with a total of 15 chronic wounds were treated with an allograft product, including Apligraf® and Dermagraft®***. Of these wounds treated with allografts, only 7% (1/15 treated wounds) remained healed after 12 weeks, and 0% (0/15 treated wounds) remained healed after 24 weeks. This is a meaningful finding of the natural history study, as there are no approved therapies for RDEB patients that demonstrate significant wound closure after two months post-application.

Investigators at Stanford University are enrolling patients for the ongoing Phase 2 portion of the Phase 1/2 clinical trial (NCT01263379). The EB-101 program has been granted orphan drug designation from the European Medicines Agency (EMA).

Image credit: Samantha Okazaki / Today

Thorough Genotyping and Repurposed Drugs Key to Treating Small-Cell Lung Cancer, says Cancer Expert

Small cell lung cancer (SCLC) is an aggressive disease characterized by quick growth and spread. While there has been a gradual decrease in incidence of SCLC in recent years, likely reflecting the decreased prevalence of tobacco use, little progress has been made in treating SCLC due to its complex pathogenesis.

The majority of patients, including those with limited-stage disease and those who initially respond to chemo- and radiation- therapy (two traditional pillars of cancer therapy), become resistant to treatment resulting in a very small percentage (approximately 6%) who survive 5 years after being diagnosed.

Smoking is the main risk factor for SCLC, with only 2-3% of patients categorized as never-smokers.

Identifying Therapeutic Targets in Small-Cell Lung Cancer

From the molecular point of view, SCLC is characterized by a multitude of alterations, owing to the fact that cells are exposed to a myriad of carcinogens contained in cigarette smoke, which bind and mutate DNA. These alterations affect numerous genes and pathways, but among these there are few obvious therapeutic targets. This means that the driver genes responsible for most SCLC development and progression have yet to be identified with any certainty.

However, new high-throughput technologies, which allow comprehensive gene profiling, have revealed promising findings. For example, 20% of SCLC patient tumors bear alterations in the MYC gene family. This discovery has helped to identify a subset of patients sensitive to an oncogenic kinase downstream in the MYC pathway, allowing for better designed, biomarker-driven clinical trials for these, often repurposed, therapeutic agents.

Similarly, PARP1 and Notch have been found overexpressed in SCLC. In order to target PARP1, an enzyme which, when it malfunctions, leads to replication of damaged DNA, researchers are currently evaluating the efficacy of PARP inhibitors for treatment of SCLC. And, to investigate targeting of the Notch signaling pathway, which influences the cellular life-cycle, the FDA is in the process of approving Tarextumab, a selective Notch inhibitor, in the treatment of SCLC.

Another issue with SCLC tumors is that they are mostly characterized by the loss of two crucial oncosuppressor genes, named RB, RB2\p130 i and TP53, which are less actionable pharmaceutically because it is much more difficult to restore a loss of function rather than block an oncogenic gain of function. Although challenging, researchers are nonetheless trying to develop strategies in this direction.

Repurposing Existing Drugs

Also important to the progress of SCLC therapies, more effective drug identification and testing, through the use of powerful mouse models of the human disease, put researchers in a good position to tackle this cancer type and attempt better defined targeted approaches.

Recent immunotherapy approaches have emerged as a significant new pillar in cancer therapy and are being assessed in numerous clinical trials for a multitude of tumors, including SCLC. In particular, two new agents, nivolumab and ipilimumab, have recently been developed to treat other forms of cancer, such as unresectable or metastatic malignant melanoma, advanced non-small-cell lung cancer (NSCLC), and advanced renal-cell carcinoma. These agents have also been tested for applications in SCLC. Nivolumab and ipilimumab are constituted by monoclonal antibodies functioning through direct inhibition of CTLA4 and PD1, respectively, which are key negative regulators of the antitumoral immune function. Bristol-Myers Squibb (BMS) was able to obtain the National Comprehensive Cancer Network indication for use of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The indication was achieved upon the publication on Lancet Oncology by Scott Antonia and colleagues, who reported the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab, achieving antitumour activity with durable responses and manageable safety profiles in previously treated SCLC patients, enrolled in the CheckMate-032 clinical trial.

Data was also presented at the World Lung Cancer Congress on the immunotherapy drug pembrolizumab, another therapeutic antibody against PD1, already approved for other diseases, which showed good efficacy.

One additional drug in this category is rovalptizumab teserine, a first-in-class antibody-drug conjugate comprised of a humanized monoclonal antibody against DLL3 and a toxin. DLL3 is a Notch ligand found to be expressed on 80% of SCLC. There is a 3rd line trial which is biomarker driven, meaning that they test for DLL3 expression and patients are eligible if they have “high” DLL3.

 

Doctors Treat Deadly Cancerous Disorders with Gene-Guided, Targeted Therapy

Genomic testing of biopsies from patients with deadly, treatment-resistant cancerous blood syndromes called histiocytoses allowed doctors to identify genes fueling the ailments and use targeted molecular drugs to successfully treat them.

Researchers from the Cincinnati Children’s Cancer and Blood Diseases Institute report their data in Journal of Clinical Investigation Insight (JCI Insight). They recommend the regular use of comprehensive genomic profiling at diagnosis to positively impact clinical care, as well as rigorous clinical trials to verify and extend the diagnostic and treatment conclusions in their study.

Histiocytoses are a group of disorders in which abnormal accumulations of white blood cells form tumors on vital organs, leading to systemic organ damage or death. About half of the patients can be treated successfully with chemotherapy, but others are treatment resistant.

Study authors conducted genomic profiling of biopsies from 72 child and adult patients with a variety of treatment-resistant histiocytoses, including the most common one in children, Langerhans cell histiocytosis (LCH), according to the lead investigator, Ashish Kumar, MD, PhD.

Twenty-six patients with treatment-resistant disease had gene mutations involving either BRAF or MAP2K1 that directly activate the MAP-kinase cancer pathway. Researchers determined such patients would benefit from the targeted molecular therapies dabrafenib or trametinib, which block the MAP kinase pathway. The approved cancer drugs were prescribed off label to the histiocytosis patients.

“In the last year, three patients we treated were infants with disease that was resistant to several rounds of intense chemotherapy. In the past, these children either would have suffered serious complications including death or would have had to endure more intensive treatments and the ensuing toxicities, including the risk of death,” Kumar said. “All three are thriving now on one oral medication that put their disease into remission.”

Potentially Reversible Changes in Gene Control ‘Prime’ Pancreatic Cancer Cells to Spread

Epigenetic changes, not DNA mutations, drive some metastasis

multicenter team of researchers reports that a full genomic analysis of tumor samples from a small number of people who died of pancreatic cancer suggests that chemical changes to DNA that do not affect the DNA sequence itself yet control how it operates confer survival advantages on subsets of pancreatic cancer cells. Those advantages, the researchers say, let such cancer cells thrive in organs like the liver and lungs, which receive a sugar-rich blood supply.

In a summary of the study, published online in the journal Nature Genetics on Jan. 16, the
research teams also report evidence that an experimental drug — not approved for human use — can reverse these “epigenetic” changes to block tumor formation in lab-grown pancreatic cancer cells. These findings may lead to more effective treatment strategies against metastatic pancreatic cancer, which is universally lethal.

“What we found astonished us,” says study leader Andrew Feinberg, M.D., Bloomberg Distinguished Professor of Epigenetics at The Johns Hopkins University and a Johns Hopkins Kimmel Cancer Center member. “Changes in genes’ regulation — not in the DNA sequence of genes themselves — were the driving force behind successful metastases in our experiments, and, as far as we know, this is the first genomewide experimental evidence for this phenomenon.”

Metastasis, or cancer spread by the formation of tumors at new sites, is generally what makes cancers deadly because surgery and other treatments are unlikely to find and destroy every cancer cell. That is particularly true, Feinberg says, for pancreatic cancer, which usually goes undetected until after it has spread. Because it is so deadly and because the number of new cases is increasing, it is predicted to be the second leading cause of cancer deaths in the western world by 2020, trailing only lung cancer, he adds. In 2016, the disease was predicted to strike an estimated 53,070 Americans and kill 41,780, according to the National Cancer Institute.

To better understand the formation of metastases in pancreatic cancer, Christine Iacobuzio-Donahue, M.D., Ph.D., professor of pathology at Memorial Sloan Kettering Cancer Center, collected tumor samples from eight patients with the most common form of pancreatic cancer (pancreatic ductal adenocarcinoma) immediately after their deaths.

Samples were taken from the original, or primary, tumor in the pancreas and from any detectable nearby and distant metastatic tumors. The tumors’ genomes were then analyzed for genetic mutations, or alterations in their DNA, by her team and that of Bert Vogelstein, M.D., professor of oncology at the Johns Hopkins University School of Medicine and the co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center. In a companion paper, they report finding no genetic mutations directly linked to or likely responsible for the success of the metastases.

Working on the same tumor samples, Feinberg’s team looked for other kinds of changes — specifically in the so-called epigenome, the array of reversible chemical and structural changes to DNA and the proteins around which it is wrapped. Epigenetic changes do not alter the information encoded in the DNA sequence itself but determine whether and to what extent specific genes are used by cells.

The research groups then examined the landscape of the pancreatic cancer epigenome using a combination of stains on patient tissues, direct examination of the proteins that wrap DNA and whole-genome sequencing of the detected epigenetic changes to map precisely where they were located.

Feinberg says no major changes were seen in the tumors of patients whose cancer spread only locally. But tumors from patients with distant metastases to the lung and liver showed massive epigenetic changes that mapped to large, blocklike segments of the genome, both in the distant metastases themselves and in the section, or “subclone,” of the primary tumors they came from.

One explanation for that, says Iacobuzio-Donahue, is that “Distant metastases have to travel long distances along the ‘highways’ of the blood vessels, land in a good spot and colonize, while local metastases just pinch off the primary tumor and go a short distance on ‘familiar side roads,’ so they are usually more similar to the primary tumor.”

Beyond pancreatic cancer, the blocklike segments where the epigenetic changes were located could be universal across other cancers. “Although we haven’t tested this idea yet, we know that similar epigenetic regions are important in other types of cancer, such as colon cancer, so it’s likely that these large-scale epigenetic changes are occurring in them too,” says Feinberg.

Because epigenetic changes affect gene activity, the research team categorized the affected genes by function to see if the changes might have specific consequences among different subclones from the same patient. This analysis, done on separate samples from the same patient, revealed that many of the affected genes confer advantages to cancer cells by, for example, enhancing cell migration or resistance to chemotherapy.

The teams next looked for what might control the epigenetic changes. Aware that cancers rewire their metabolism in ways that could change the epigenome and that distant metastases in pancreatic cancer naturally spread to organs fed by a sugar-rich blood supply, the researchers wondered if the tumor cells had altered the way they use the basic form of sugar, glucose.

In biochemical tests, they learned that distant metastatic tumors consumed excessive amounts of glucose when compared to local metastases. They also found that distant metastases and their precursors processed glucose through a growth-promoting series of metabolic reactions called the pentose phosphate pathway, which burns (or oxidizes) glucose-derived molecules into building blocks for tumors. Particularly important was an enzyme called 6-phosphogluconate dehydrogenase (PGD).

Those results may answer another poorly understood question about metastatic cancer biology, the researchers report. Oliver McDonald, M.D., Ph.D., assistant professor of pathology, microbiology and immunology at Vanderbilt University and co-first author of the study, says: “In pancreatic cancer, the fact that it may take years for a primary tumor to develop, while metastases can progress very quickly, is somewhat of an enigma. The changes we found in glucose utilization could be the answer.”

To see if PGD and the pentose phosphate pathway were tied to the epigenetic changes the researchers had detected in distant metastases, they treated tumor cells from different sites in a single patient with the drug 6-aminonicotinamide (6AN), which is known to inhibit PGD but is not used in humans because of its severe side effects. The drug had no effect on the epigenetic state of DNA taken from the local metastasis but reversed the epigenetic changes seen in cells from the distant metastasis.

Significantly, treatment with 6AN specifically decreased the activity of genes with malignant, cancer-spreading functions, like cell cycle control and DNA repair. But most importantly, the researchers say, in three laboratory tests of tumor growth, the drug strongly blocked tumor formation in distant metastases and their precursors.

The investigators caution that application of their findings to the treatment of pancreatic cancer must await further understanding of the complicated genetics and biology of metastases. “We still don’t know how the pentose phosphate pathway gets turned on, for example,” says McDonald, “but we’re working on figuring it out.”

Feinberg adds that the groups are also trying to learn how activation of the pentose phosphate pathway leads to the massive epigenetic changes seen. “Hopefully, these investigations will help develop new drugs to treat this aggressive cancer and others,” he says.

Other authors of the report include Xin Li, Rakel Tryggvadottir and Tal Salz of the Johns Hopkins University School of Medicine; Anna Word, Sonoko Natsume and Kimberly Stauffer of Vanderbilt University Medical Center; Tyler Saunders, Alvin Makohon-Moore and Yi Zhong of Memorial Sloan Kettering Cancer Center; Samantha Mentch, Marc Warmoes and Jason Locasale of Duke University School of Medicine; Alessandro Carrer and Kathryn Wellen of the University of Pennsylvania Perelman School of Medicine; and Hao Wu of Emory University.

Gut Bacteria May Hold Key to Treating Autoimmune Disease

Defects in the body’s regulatory T cells (T reg cells) cause inflammation and autoimmune disease by altering the type of bacteria living in the gut, researchers from The University of Texas Health Science Center at Houston have discovered. The study, “Resetting microbiota by Lactobacillus reuteri inhibits T reg deficiency–induced autoimmunity via adenosine A2A receptors,” which will be published online December 19 in The Journal of Experimental Medicine, suggests that replacing the missing gut bacteria, or restoring a key metabolite called inosine, could help treat children with a rare and often fatal autoimmune disease called IPEX syndrome.

T reg cells suppress the immune system and prevent it from attacking the body’s own tissues by mistake. Defects in T reg cells therefore lead to various types of autoimmune disease. Mutations in the transcription factor Foxp3, for example, disrupt T reg function and cause IPEX syndrome. This inherited autoimmune disorder is characterized by a variety of inflammatory conditions including eczema, type I diabetes, and severe enteropathy. Without a stem cell transplant from a suitable donor, IPEX syndrome patients usually die before the age of two.

Autoimmune diseases can also be caused by changes in the gut microbiome, the population of bacteria that reside within the gastrointestinal tract. In the study, the team led by Yuying Liu and J. Marc Rhoads at The University of Texas Health Science Center at Houston McGovern Medical School find that mice carrying a mutant version of the Foxp3 gene show changes in their gut microbiome at around the same time that they develop autoimmune symptoms. In particular, the mice have lower levels of bacteria from the genus Lactobacillus. The researchers discovered that by feeding the mice with Lactobacillus reuteri, they could “reset” the gut bacterial community and reduce the levels of inflammation, significantly extending the animals’ survival.

Bacteria can secrete metabolic molecules that have large effects on their hosts. The levels of a metabolite called inosine were reduced in mice lacking Foxp3 but were restored to normal after resetting the gut microbiome with L. reuteri. The researchers found that, by binding to cell surface proteins called adenosine A2A receptors, inosine inhibits the production of Th1 and Th2 cells. These pro-inflammatory T cell types are elevated in Foxp3-deficient mice, but their numbers are diminished by treatment with either L. reuteri or inosine itself, reducing inflammation and extending the animals’ life span.

“Our findings suggest that probiotic L. reuteri, inosine, or other A2A receptor agonists could be used therapeutically to control T cell–mediated autoimmunity,” says Yuying Liu.

Conflict of interest statement: Some of the authors of this study, including Yuying Liu and J. Marc Rhoads, have a patent application pending on use of inosine and A2A agonists in IPEX syndrome.

After One Dose of Gene Therapy, Hemophilia B Patients Maintain Near-Normal Levels of Clotting Factor

At ASH Meeting, CHOP Hematologist Leads Clinical Trial in Which All Subjects Safely Maintain Factor IX Expression that Curtails Disabling Bleeding

Researchers are reporting the highest and most sustained levels to date of an essential blood-clotting factor IX in patients with the inherited bleeding disorder hemophilia B. After receiving a single dose of an experimental gene therapy in a clinical trial, patients with hemophilia produced near-normal levels of clotting factor IX, allowing them to stop clotting factor infusions and to pursue normal activities of daily life without disabling bleeding episodes.

Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia (CHOP)is the lead investigator of the phase 1/2 clinical trial sponsored by Spark Therapeutics, Inc. and Pfizer, Inc. The American Society of Hematology (ASH) today highlighted updated findings from that trial in a press conference during its annual meeting in San Diego. George will present those study results tomorrow at an ASH plenary scientific session.

Katherine High, MD, a senior author of the study and Spark Therapeutics’s president and chief scientific officer, described the updated interim trial data at today’s press conference. The clinical trial of nine adult hemophilia B patients, aged 18 to 52 years, used a single dose of a gene therapy product engineered to enter patients’ liver cells and direct the production of the blood clotting factor that they lack.

George notes, “Our goal in this trial was to evaluate the safety of the gene therapy product and secondarily, to determine if we could achieve levels of factor IX that could decrease bleeding events in patients.” She added, “These patients have a severe or moderate level of hemophilia, with baseline clotting factor level less than or equal to 2 percent of levels in healthy people. In current treatment, patients with hemophilia give themselves intravenous doses of factor IX up to a couple times a week. While generally effective, factor levels fluctuate, and patients may suffer painful, disabling joint bleeds when their clotting factor levels drop. Such a regimen requires significant planning of daily activities.”

In the current trial, said George, the patients maintained factor levels of approximately 30 percent, enough to lift them out of the severe category. “At these new levels, hemophilia patients do not typically need to self-treat with factor to avoid bleeding events,” she said, adding, “This represents a potential dramatic improvement in their quality of life and a shift in the way we think about treating hemophilia.” A factor level of 30 percent is near-normal, she added, and patients would be expected to experience bleeding only in the event of major trauma or surgery.

One subject self-infused two days after receiving the gene therapy vector. Beyond this, no patients had any bleeding events or required factor for any reason. With significant reduction in bleeding events and factor use, six of the first seven patients reported increased physical activity and all reported improved quality of life. Two additional patients received the gene therapy product too recently to determine quality-of-life measures.

Previous hemophilia gene therapy trials have been frustrated by an immune response to the gene therapy product that limited the success of the therapy. In the current trial, two patients experienced an immune response to the gene therapy that did not result in safety concerns, and were treated with steroids. The patients are still undergoing treatment but have maintained factor IX activity without bleeding.

George reported that she is cautiously optimistic, acknowledging that this trial is a small study, with a short follow-up period as yet. However, as the researchers continue to monitor patients in the current trial, next steps will be to discuss with the U.S. Food and Drug Administration the outlines of a larger, phase 3 clinical trial. No gene therapies for any genetic diseases have yet been approved for clinical use in the U.S.

Formerly a research leader at CHOP, High pursued groundbreaking preclinical investigations in hemophilia B gene therapy and provided scientific expertise to previous gene therapy trials in hemophilia and other genetic disorders at CHOP before moving to Spark Therapeutics, which was spun off from CHOP in 2013. CHOP maintains a financial interest in the company.

Successfully Treating Genetically Determined Autoimmune Enteritis

Using targeted immunotherapy, doctors have succeeded in curing a type of autoimmune enteritis caused by a recently discovered genetic mutation. This report comes from researchers at the Department of Biomedicine of the University of Basel and University Hospital Basel. Their results raise new possibilities for the management of diarrhea, which is often a side effect of melanoma treatment.

Immunodeficiencies can arise due to gene mutations in immune system proteins. As such mutations rarely occur, these immunodeficiencies often go unrecognized or are detected too late for effective treatment. Currently, there are more than 300 different known genetically determined immunodeficiencies, with new examples being described almost every week.

Prof. Mike Recher’s research group at the Department of Biomedicine of the University of Basel and University Hospital Basel recently discovered a genetic immunodeficiency associated with serious, chronic autoimmune enteritis in an adult patient. Happily, according to the researchers’ report in the Journal of Allergy and Clinical Immunology, they were able not only to describe the new mutation, but also to successfully treat the patient with targeted therapy.

Autoimmune reaction caused by mutation

The patient had a rare mutation in the CTLA-4 protein found on the surface of T-cells. Normally, this protein prevents immune cells from attacking an patient’s own body. However, as it was not functioning adequately due to the mutation, T-cells attacked the patient’s own intestinal cells, causing chronic inflammation. This resulted in the patient suffering from severe diarrhea and weight loss.

These unusual symptoms led the cantonal hospital of Graubünden to refer the patient to the special clinic for immunodeficiency at the University Hospital Basel. Initial immunological investigations suggested a genetically determined dysregulation of the immune system. The new CTLA-4 gene mutation was discovered following subsequent analysis of the entire genome at the University Hospital Zurich. Further investigations showed that the mutation causes reduced CTLA-4 function, which led to increased infiltration of the intestinal mucosa by T-cells and therefore to chronic diarrhea.

Treatment with therapeutic antibodies

Working in close cooperation with University Hospital Basel’s gastroenterology department, the doctors opted for a therapy that uses a new drug from the monoclonal antibody group to prevent the T-cells from penetrating the intestinal mucosa. This drug (vedolizumab) blocks a specific adhesion molecule on the surface of the T-cell and thereby inhibits immune cells from binding themselves to receptors present in the intestine, preventing the T-cells from penetrating the blood vessels in the intestinal tissue. This treatment produced the desired outcome: after three months, the patient’s chronic diarrhea had stopped completely.

Preventing diarrhea in melanoma patients

In some diseases, however, CTLA-4 inhibition can be used therapeutically, as in the treatment of skin cancer (melanoma). The drug Ipilimumab works similarly to the CTLA-4 mutation, meaning that immune system T-cells are no longer properly inhibited and can more efficiently attack the malignant skin cancer cells. One of the side-effects of this therapy is autoimmune intestinal inflammation – analogous to the inflammation that occurs in patients with the CTLA-4 gene mutation. It is possible that melanoma patients, who suffer severe diarrhea due to the inhibition of their CTLA-4 function, will benefit from this new insight, which opens up new therapeutic possibilities for Vedolizumab.

Cooperation between regional hospitals, basic research and university medical departments

This case demonstrates the importance of precise diagnosis of the molecular causes of an illness in enabling targeted, personalized treatment. “In order to expand our knowledge in these areas, doctors in clinics and regional hospitals must be on the alert for unusual disease phenotypes and refer such patients to specialized university hospital clinics for further evaluation,” says study author Mike Recher. “We also need clinical university centers that are closely linked to research laboratories.”

Researching Proinsulin Misfolding to Understand Diabetes

  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.

Gene therapy for blistering skin disease appears to enhance healing in clinical trial

Grafting sheets of a patient’s genetically corrected skin to open wounds caused by the blistering skin disease epidermolysis bullosa appears to be well-tolerated and improves wound healing, according to a phase-1 clinical trial conducted by researchers at the Stanford University School of Medicine.

The results mark the first time that skin-based gene therapy has been demonstrated to be safe and effective in patients.

The findings will be published Nov. 1 in JAMA. Associate professors of dermatology Peter Marinkovich, MD, and Jean Tang, MD, PhD, share senior authorship of the study. Senior scientist Zurab Siprashvili, PhD, is the lead author.

For the study, four adult patients with recessive dystrophic epidermolysis bullosa, an excruciatingly painful genetic skin disease, received the skin grafts.

“Our phase-1 trial shows the treatment appears safe, and we were fortunate to see some good clinical outcomes,” said Tang. “In some cases, wounds that had not healed for five years were successfully healed with the gene therapy. This is a huge improvement in the quality of life for these people.”

People with epidermolysis bullosa lack the ability to properly produce a protein called type-7 collagen that is needed to anchor the upper and lower layers of the skin together. As a result, the layers slide across one another upon the slightest friction, creating blisters and large open wounds. The most severe cases are fatal in infancy. Other patients with recessive dystrophic EB can live into their teens or early adulthood with supportive care. Often these patients die from squamous cell carcinoma that develops as a result of constant inflammation in response to ongoing wounding.

The Stanford researchers showed that it was possible to restore functional type-7 collagen protein expression in patient skin grafts to stop blistering and allow wounds to heal. They also found that the protein continued to be expressed and that wound healing was improved during a year of follow up.

Looking to build upon results

The researchers seek to build upon these promising early results in a new trial that will include patients ages 13 and older.

“Moving into the pediatric population may allow us to intervene before serious chronic wounds and scars appear,” said Marinkovich, who directs the Stanford Blistering Disease Clinic. Repeated rounds of wounding and scarring on the fingers and palms, for example, often lead to fusion of the skin and the formation of what’s known as a “mitten hand.”

Siprashvili used a virus to deliver a corrected version of the type-7 collagen gene into batches of each patient’s skin cells that had been harvested and grown in the laboratory. He coaxed these genetically corrected cells to form sheets of skin about the size of an iPhone 5. The sheets were then surgically grafted onto the patient’s chronic or new wounds in six locations.

The researchers tracked the status of the grafts at one-, three- and six-month intervals for at least a year, checking to see if they stayed in place and caused wound closure. They also looked for any evidence of an immune reaction to the grafts, and whether the grafts continued to make the corrected type-7 collagen protein.

All 24 grafts were well-tolerated, the researchers found. Furthermore, they could detect expression of the type-7 collagen protein in the correct location of the skin in nine out of 10 tissue biopsies at three months. After 12 months, they were able to detect the collagen protein in five out of 12 biopsies.

Wound healing

Similar results were seen with wound healing. After three months, 21 of the 24 grafts were intact. This number dropped to 12 out of 24 after one year.

“Even a small improvement in wound healing is a huge benefit to the overall health of these patients,” said Tang. “For example, it may reduce the likelihood of developing squamous cell carcinoma that often kills these patients in young adulthood.”

Coupling grafts with hand surgery to break up scarred, fused tissue could help patients maintain the use of their hands, Marinkovich said.

Tang, Marinkovich and their colleagues will continue to monitor the patients in the phase-1 trial throughout their lifetimes to assess any long-term effects of the grafts.

The completion of the phase-1 trial and the potential to improve upon these outcomes is due to a concerted, long-term effort at Stanford to find ways to help young patients with this devastating disease.

The researchers are now starting a phase-2 clinical trial and are looking for new patients. For more information, send an email to tangy@stanford.edu or mpm@stanford.edu.

“This trial represents the culmination of two decades of dedicated clinical and basic science research at Stanford that began with the arrival of the former dean of the School of Medicine, Eugene Bauer, who set up the multidisciplinary EB Center at Stanford,” said Tang. “We have been working for a long time to get to this potential therapy into patients. We had to discover the genes and proteins involved and the responsible mutations. We then had to learn to deliver the corrected gene and grow those cells into sheets suitable for grafting.”

“We could not have reached this point without the support of the EB patients and their families,” said Marinkovich. “Since the time of my research training in the laboratory of Robert Burgeson, PhD, who discovered type-7 collagen, I’ve been deeply motivated to contribute to the EB community, and it is very satisfying to be able to finally see this molecular therapy come to fruition.”

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

New Treatment Leaves Liver Cancer Cells In Limbo

Scientists have shown that a mutation in a gene called Arid1b can cause liver cancer. The gene normally protects against cancer by limiting cell growth, but when mutated it allows cells to grow uncontrollably. The researchers have shown that two existing drugs can halt this growth in human cells. This points to a new approach to treating liver cancer.

These early results could be translated into a treatment relatively quickly, says Jesus Gil of the MRC Clinical Sciences Centre (CSC), based at Imperial College London, and who led the study. This is because the drugs are already used to treat other types of cancer. Gemcitabine is used on bladder, pancreas and ovary cancer, whilst DON has been tested in clinical trials. Both are known to be safe in people so will not require the usual toxicity testing.

According to MacMillian Cancer Support, 4200 people in the UK are diagnosed with liver cancer annually. “Liver cancer is a deadly disease,” says Luca Tordella, a postdoctoral researcher at the CSC who played a key role in the study. He says the new treatment will be most effective in people who have a mutation in the Arid1b gene. “It’s important to better classify patients into groups, according to their genes. One advance of personalised medicine is to understand which drug will work best on you, and which on me.”

The CSC team began by looking for mutations in the DNA of 100 people with liver cancer. They focused in on genes known to regulate a cellular state called senescence. This is a built-in safety mechanism that helps to protect the cell against cancer. Senescence is triggered when a cell grows abnormally fast and, once induced, it acts to keep the cell in limbo, such that it is alive but can no longer grow or divide. Bypassing senescence is a hallmark of many types of cancer.

It has previously been suggested that the Arid1b gene plays a role in liver cancer. The CSC team are the first to show that it does so by disrupting senescence. Working with researchers at the University of Tübingen, Germany, they mutated Arid1b in mice and human cells, and this stopped the cells from entering senescence. When Arid1b was mutated in mice that also had a mutation in the gene Ras, the mice developed liver cancer.

The researchers also identified exactly how Arid1b stimulates senescence. In healthy cells, Arid1b is part of a bigger complex (called SWI/SNF) that regulates the activity of hundreds of genes. One of these genes produces an enzyme that breaks down the building blocks of DNA. Without these blocks, the cell cannot continue to grow and divide so enters senescence. But if Arid1b is mutated, the blocks cannot be degraded and the cell continues to grow, bypassing senescence and potentially growing out of control.

Gil and Tordella have shown that it’s possible to induce senescence by treating human cells, which have an Arid1b mutation, with either gemcitabine or DON. Both drugs inhibit the synthesis of these blocks, called nucleotides, and thereby induce senescence and stop cancer in its tracks.

“Around 20% of patients with liver cancer have mutations on the genes encoding for components of the SWI/SNF complex. What we suggest is if we treat these people with drugs that target the degradation of nucleotides, they will respond,” says Gil. “We plan to continue to research this in the lab to develop treatments to target liver cancer.”

Asthma Research Unexpectedly Yields New Treatment Approach For Inherited Enzyme Disease

Experiments designed to reveal how a protein protects the lungs from asthma-related damage suggest a new way to treat a rare disease marked by the inability of cells to break down fats, according to a report in EBioMedicine published online Oct. 25.

The study results address Gaucher’s disease, which is caused by a genetic glitch in cell structures called lysosomes that process fats and remove cellular waste. Found mostly in Jews of Eastern and Central European origin, the condition may come with joint pain, blood disorders, enlarged spleens and livers, memory loss, and lung damage.

At a cellular level, Gaucher’s disease is associated with abnormally low production of the protein progranulin, as well as with the misplaced buildup of the enzyme beta-glucocerebrosidase, or GBA, outside lysosomes, instead of inside where it is needed.

Led by researchers from NYU Langone Medical Center, the new study found that a manufactured version of progranulin reversed most effects of Gaucher’s disease in mouse and human cell studies, including GBA accumulation.

“Our results suggest a new way to treat Gaucher’s disease that corrects abnormal enzyme delivery by progranulin to lysosomes, as opposed to current treatment strategies that temporarily replenish lysosomal GBA stores, which are then steadily consumed,” says senior study investigator Chuanju Liu, PhD, a professor in the Departments of Orthopaedic Surgery and Cell Biology at NYU Langone. The research team and NYU Langone hold a patent on related, potential therapies.

Among the study’s other key findings was that progranulin must bind to other molecules to transport the enzyme to lysosomes, specifically the protective “heat shock” protein 70. If unshielded, cellular GBA molecules fold up and stick together outside lysosomes.

Researchers also found that adding synthetic progranulin, or Pcgin, to blood cells obtained from patients with Gaucher’s, led to a 40 percent reduction in GBA clumping within a week. Pcgin was used because it is chemically more stable than progranulin and poses no risk of uncontrolled tumor-like cell growth in test animals, say the authors.

“Our new experiments are the first to explain why reduced progranulin is a key characteristic of Gaucher’s, and why the mice engineered to lack the protein serve as such a good model to test new therapies,” says lead study investigator Jian Jinlong, MD, PhD, an associate research scientist at NYU Langone.

Along with their role in brain disorders, progranulin shortages had been tied by previous research to cell swelling in asthmatic lungs. In the current set of experiments in progranulin-deficient mice, adding Pcgin reduced lung-tissue swelling by as much as 60 percent, an effect seen with current GBA-replacement treatments.

According to Liu, further research is needed to determine the precise mechanism by which progranulin reduces cell swelling, a process that would likely yield even more drug targets for Gaucher’s disease.

Experts estimate that as many as one in 50,000 Americans has some form of Gaucher’s, while one in 500 Jews of Ashkenazi descent has the disease.

Genome Engineering Paves The Way For Sickle Cell Cure

A team of physicians and laboratory scientists has taken a key step toward a cure for sickle cell disease, using CRISPR-Cas9 gene editing to fix the mutated gene responsible for the disease in stem cells from the blood of affected patients.

For the first time, they have corrected the mutation in a proportion of stem cells that is high enough to produce a substantial benefit in sickle cell patients.

The researchers from the University of California, Berkeley, UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI) and the University of Utah School of Medicine hope to re-infuse patients with the edited stem cells and alleviate symptoms of the disease, which primarily afflicts those of African descent and leads to anemia, painful blood blockages and early death.

“We’re very excited about the promise of this technology,” said Jacob Corn, a senior author on the study and scientific director of the Innovative Genomics Initiative at UC Berkeley. “There is still a lot of work to be done before this approach might be used in the clinic, but we’re hopeful that it will pave the way for new kinds of treatment for patients with sickle cell disease.”

In tests in mice, the genetically engineered stem cells stuck around for at least four months after transplantation, an important benchmark to ensure that any potential therapy would be lasting.

“This is an important advance because for the first time we show a level of correction in stem cells that should be sufficient for a clinical benefit in persons with sickle cell anemia,” said co-author Mark Walters, a pediatric hematologist and oncologist and director of UCSF Benioff Children’s Hospital Oakland’s Blood and Marrow Transplantation Program.

The results will be reported in the Oct. 12 issue of the online journal Science Translational Medicine.

Sickle cell disease is a recessive genetic disorder caused by a single mutation in both copies of a gene coding for beta-globin, a protein that forms part of the oxygen-carrying molecule hemoglobin. This homozygous defect causes hemoglobin molecules to stick together, deforming red blood cells into a characteristic “sickle” shape. These misshapen cells get stuck in blood vessels, causing blockages, anemia, pain, organ failure and significantly shortened lifespan. Sickle cell disease is particularly prevalent in African Americans and the sub-Saharan African population, affecting hundreds of thousands of people worldwide.

The goal of the multi-institutional team is to develop genome engineering-based methods for correcting the disease-causing mutation in each patient’s own stem cells to ensure that new red blood cells are healthy.

The team used CRISPR-Cas9 to correct the disease-causing mutation in hematopoietic stem cells – precursor cells that mature into red blood cells – isolated from whole blood of sickle cell patients. The corrected cells produced healthy hemoglobin, which mutated cells do not make at all.

Future pre-clinical work will require additional optimization, large-scale mouse studies and rigorous safety analysis, the researchers emphasize. Corn and his lab have joined with Walters, an expert in developing curative treatments such as bone marrow transplant and gene therapy for sickle cell disease, to initiate an early-phase clinical trial to test this new treatment within the next five years.

Notably, research groups might be able to apply the approach described in this study to develop treatments for other blood diseases such as β-thalassemia, severe combined immunodeficiency (SCID), chronic granulomatous disease, rare disorders like Wiskott-Aldrich syndrome and Fanconi anemia, and even HIV infection.

“Sickle cell disease is just one of many blood disorders caused by a single mutation in the genome,” Corn said. “It’s very possible that other researchers and clinicians could use this type of gene editing to explore ways to cure a large number of diseases.”

“There is a clear path for developing therapies for certain diseases,” said co-senior author Dana Carroll of the University of Utah, who co-developed one of the first genome editing techniques over a decade ago. “It’s very gratifying to see gene editing technology being brought to practical applications.”

The work is the fruit of the Innovative Genomics Initiative, a joint effort between UC Berkeley and UCSF that aims to correct DNA mutations that underlie human disease using CRISPR-Cas9, a pioneering technology co-developed by scientists at UC Berkeley that has made genome editing easier and more efficient than ever before.

Smallest-Reported Artificial Virus Could Help Advance Gene Therapy

Gene therapy is a kind of experimental treatment that is designed to fix faulty genetic material and help a patient fight off or recover from a disease. Now scientists have engineered the smallest-reported virus-like shell that can self-assemble. It could someday carry potentially therapeutic DNA or RNA and transfer it to human cells. The report appears in the Journal of the American Chemical Society.

The story of gene therapy is fraught with much hype and high-profile failures. But, hype and failures aside, it remains a promising route to treat a range of ailments, from rare genetic diseases to common conditions such as diabetes. Clinical trials to test various gene therapy treatments are underway. One possible approach is to copy the way viruses behave. When they infect people, viruses inject their genetic material into human cells. Artificial viruses have been engineered to mimic this step, but they tend to clump or are not uniform in size, which can hinder their effectiveness. Max Ryadnov and colleagues wanted to address these issues.

Rather than using full proteins, the researchers used short peptide sequences designed to assemble into tiny gene carriers, which are smaller than previously reported synthetic viruses and even naturally occurring viruses. Lab testing showed that their artificial viral shells were uniform in size and didn’t clump. The particles could encase DNA or RNA and transfer the genetic material to human cells without harm. Depending on the introduced material, the recipient cells then either expressed a new protein or stopped expressing their own protein.

Gene Therapy Company Acquires Next Generation AAV Gene Therapy Vector Platform from The University of North Carolina at Chapel Hill

The University of North Carolina at Chapel Hill has licensed the exclusive worldwide rights of a next generation gene therapy AAV capsid portfolio to Abeona Therapeutics Inc., a clinical-stage biopharmaceutical company focused on developing therapies for life-threatening rare genetic diseases. The AIM vector system is a next generation platform of AAV capsids capable of widespread central nervous system gene transfer and can be used to confer high transduction efficiency for various therapeutic indications.

Studies indicate that AIM vectors can efficiently and broadly target CNS tissue, and may provide a treatment for patients that have inhibitory antibodies to natural AAV serotypes. Importantly, the AIM vector system may provide second-generation treatment approaches for patients that have received a previous AAV injection.

“As we continue to build out our orphan and rare disease drug portfolio and move additional programs into the clinic, this agreement with UNC continues the execution of our strategy to combine our expertise in advancing gene therapy programs with the development of a next-generation proprietary AAV vector platform,” stated Steven H. Rouhandeh, Executive Chairman. “We look forward to harnessing the clinical utility and therapeutic potential of the AIM vector system technology platform to address a broad range of rare genetic diseases.”

In addition to the AAV capsid library, the license also adds ABO-202, an AAV-based CLN1 program, to Abeona’s Batten pipeline.  ABO-202, developed at UNC by Steven Gray, Ph.D. with the support of The Saoirse Foundation, Taylor’s Tale, Hayden’s Batten Disease Foundation, and the Batten Disease Support and Research Association, is anticipated to enter clinical trials in 2017 for patients with infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease), an inherited fatal genetic disease that primarily affects the nervous system.

Infantile neuronal ceroid lipofuscinosis (INCL) CLN1, also known as PPT1, encodes an enzyme called palmitoyl-protein thioesterase 1 that is insufficiently active in Infantile NCL. Infantile NCL (INCL or Santavuori-Haltia disease) begins between about ages 6 months and 2 years and progresses rapidly. Affected children fail to thrive and have microcephaly. Also typical are short, sharp muscle contractions called myoclonic jerks. These children usually do not reach age 5.

“ABO-202 has shown promising preclinical efficacy in INCL mice after delivery of a functioning copy of the CLN1 gene to cells of the central nervous system, by extending survival and preserving strength when administered early in the disease course,” noted Steven J. Gray, Ph. D, Assistant Professor, Department of Ophthalmology, Gene Therapy Center, University of North Carolina at Chapel Hill. “Our work in developing these novel, next generation AAV gene therapy vectors have the potential to further advance the field of AAV-based technologies by efficiently and specifically targeting the CNS, with a likelihood of avoiding antibodies endogenously generated by natural AAV serotypes.”

“The AIM vector system is a next generation AAV-based gene therapy technology platform that represents a transformational opportunity for Abeona. The AIM platform will allow us to leverage our current pipeline into second generation products for CNS and other tissue-specific delivery, and help provide an answer for patients that have existing inhibitory antibodies,” stated Timothy J. Miller, Ph.D., President & CEO. “In addition, we add another AAV-based product ABO-202 (AAV-CLN1) for treatment of patients with infantile neuronal ceroid lipofuscinosis (INCL), which builds on our expertise in developing treatments for patients with forms of Batten disease.”

New Collaboration focuses on Gene Therapy to Tackle Epidermolysis Bullosa (EB) Treatments

Abeona Therapeutics Inc., a clinical-stage biopharmaceutical company focused on delivering gene and plasma-based therapy for life-threatening rare diseases, EB Research Partnership (EBRP) and EB Research Medical Foundation (EBMRF) announced today a collaboration focusing on gene therapy treatments for epidermolysis bullosa (EB), a group of devastating rare genetic skin disorders impacting children; characterized by skin blisters and erosions all over the body.

Phase 1 clinical trial results for the lead EB program, EB-101 for the treatment of recessive dystrophic epidermolysis bullosa (RDEB), were recently presented at the opening Plenary Session of the Society for Investigative Dermatology in May 2016. Investigators at Stanford are recruiting patients for a Phase 2 trial to begin soon. These novel gene therapy products were developed at the Stanford University School of Medicine and are exclusively licensed to Abeona.

“The addition of the EB gene therapy programs to our clinical pipeline advances our mission of serving those impacted by rare disease. The strong Phase 1 clinical data demonstrate safety and initial efficacy one-year post treatment, and support a follow-on Phase 2 trial for children suffering from EB,” said Timothy Miller, PhD., President and CEO of Abeona Therapeutics.

“This collaboration builds on our strengths in developing gene therapies for devastating rare diseases in partnership with patient groups and academic research centers,” said Steven H. Rouhandeh, Executive Chairman of Abeona Therapeutics. “We are proud to work with the EB Research Partnership, EB Medical Research Foundation and Stanford University to accelerate these promising product candidates towards commercialization.”

 “This collaboration exemplifies the mission of EBRP to advance commercially sustainable research aimed at treating and ultimately curing epidermolysis bullosa,” stated Alexander Silver, co-founder and Chairman, EBRP. “We believe that Abeona can fully realize our mission of progressing research insights from academia into life-changing treatment solutions for EB patients and their families.  This partnership also validates EBRP’s venture philanthropy model, which is important in getting treatments to patients as soon as possible.  We are thankful to the team at Stanford for all their hard work and assistance in forming this partnership.”

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe inherited blistering skin disease caused by absence of a protein known as type VII collagen. Patients with RDEB develop large, severely painful blisters and chronic wounds from minor trauma to their skin and there are currently no FDA approved treatments. The Phase 1 clinical trial with gene-corrected skin grafts has shown promising wound healing and safety in adult patients with RDEB. Investigators at Stanford are now recruiting patients for a Phase 2 trial with EB-101 in adolescents age 13 and older to determine the effect of type VII collagen gene-corrected grafts on wound healing efficacy.

Epidermolysis Bullosa (EB): EB is a group of devastating, life-threatening genetic skin disorders impacting children that is characterized by skin blisters and erosions all over the body. One of the most severe forms is recessive dystrophic epidermolysis bullosa (RDEB) characterized by chronic skin blistering, open and painful wounds, joint contractures, esophageal strictures, pseudosyndactyly, corneal abrasions, and a shortened life span. Patients with RDEB lack functional type VII collagen owing to mutations in the gene COL7A1 that encodes for C7. C7 is the main component of anchoring fibrils that attach the dermis to the epidermis. EB patients suffer through intense pain throughout their lives, with few or no effective treatments available to reduce the severity of their symptoms. Along with the life-threatening infectious complications associated with this disorder, many individuals will develop an aggressive form of squamous cell carcinoma (SCC). Abeona’s lead EB product, EB-101 (gene-corrected skin grafts), is a gene therapy currently in clinical trials for the treatment of RDEB patients.

Image credit: Debra International

Genetic Profiling Increases Cancer Treatment Options, Sanford Study Finds

Genetic profiling of cancer tumors provides new avenues for treatment of the disease, according to a study conducted by Sanford Health and recognized by the American Society of Clinical Oncology.

In 2014, Sanford developed and launched the Genetic Exploration of the Molecular Basis of Malignancy in Adults, or GEMMA, to determine if evaluating genetic information could help customize treatment options for adult patients whose cancer had progressed after the first line of treatment or was too rare for standard treatment. DNA was extracted from tumor samples and tested to identify targets for treatment.

Oncologist and cancer researcher Steven Powell, M.D., and his team used next-generation gene sequencing technology to analyze tumor samples for more than 100 patients. More than 90 percent of those patients had gene mutations that could impact their treatment, Powell reported. Some patients, for example, discovered they were eligible for a clinical trial or might benefit from other personalized medicine therapies. Nearly 40 percent of these patients were able to be treated with personalized therapies as a result of their testing. Many were treated on clinical trials with new drugs that previously would not have been available to them in this region.

“Molecular profiling programs like GEMMA don’t typically experience this degree of success,” said Powell. “Sixteen percent of our patients were able to go on clinical trials matching them to a personalized therapy; many academic centers are only able to do this five percent of the time. Our numbers indicate that the development of a molecular profiling program in a community setting in the Midwest is not only feasible but effective in getting patients access to the newest treatments.”

Enrollment concluded in late 2015, and results of GEMMA were outlined in an abstract published in conjunction with this year’s American Society of Clinical Oncology Annual Meeting held in Chicago last month. The published abstract can be found on the ASCO website.

Later this year, Sanford will begin the second version of GEMMA, which will integrate molecular profiling as part of standard cancer care. The study is called Community Oncology Use of Molecular Profiling to Personalize the Approach to Specialized Cancer Treatment at Sanford, or COMPASS. Sanford experts will analyze treatment plans based on molecular profiling to determine if outcomes improve. As part of GEMMA and COMPASS, the Sanford team has brought in more than 60 different personalized therapy options for patients through clinical trials in the past two years.

Case Western Reserve University Receives NIH Funding to Participate in Launch of Genomics Center on Alzheimer’s Disease

Case Western Reserve University School of Medicine is one of six recipients of a five-year, $10.8 million award from the National Institute on Aging, part of the National Institutes of Health, to establish the Coordinating Center for Genetics and Genomics of Alzheimer’s disease.

The hope is that discovering genetic risk and prevention factors will enable and accelerate development of prevention and treatments.

The project is a joint venture of researchers from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia and five other institutions, including Case Western Reserve. The other four sites are Boston University, Columbia University, the University of Miami, and the Indiana University. It is part of the NIH Alzheimer’s Disease Sequencing Project, a project involving the same six institutions that began in 2012.

The Coordinating Center for Genetics and Genomics of Alzheimer’s disease will include genomic sequence data from thousands of people with Alzheimer’s disease as well as older cognitively normal subjects. Genome sequencing entails mapping out the order of chemical letters in a cell’s DNA. The goal is to identify genes that contribute to or help guard against Alzheimer’s disease. This work is done using highly sophisticated technology and statistical analysis.

“Understanding Alzheimer’s disease requires massive amounts of data,” said Jonathan Haines, PhD, chair of the department of epidemiology and biostatistics, and director of the Institute for Computational Biology at Case Western Reserve University School of Medicine, where much of the data analysis will occur. “By enabling us to create a common database to which potentially hundreds of researchers will have access, this funding will allow critical sharing of information and interpretation, which is essential for making progress against this insidious disease.”

William S. Bush, PhD, assistant professor of epidemiology and biostatistics at the School of Medicine, is participating in the project as well.

Haines and Bush will use their analytical and biomedical informatics expertise in this project in two ways. First, they will analyze the possible effects of multiple genes in helping cause or prevent Alzheimer’s. Second, they will provide guidance in connecting and interpreting the Alzheimer’s data with data from over 30 different databases of biological knowledge. This includes looking at correlations between the Alzheimer’s data and genes for: 1) other traits and medical conditions and 2) more basic biological mechanisms, such as determining if possible Alzheimer’s-related genes are even expressed — active — in the brain. “Placing our new statistical findings within the current understanding of Alzheimer’s disease biology is essential to move towards new therapies and preventions,” said Bush.

The Alzheimer’s Association defines Alzheimer’s as “a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.” It affects as many as five million people age 65 and older in the United States.

Current drugs are only minimally effective in reducing the severity and progression of the disease. There are no known ways to prevent Alzheimer’s disease.

The new center comprises a major part of the NIH’s National Plan to Address Alzheimer’s Disease to prevent and effectively treat Alzheimer’s disease by 2025.

Four NCI Cancer Centers Announce Landmark Research Consortium and Collaborations with Celgene

The Abramson Cancer Center at the University of Pennsylvania, The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai announced the establishment of a research consortium focused on accelerating the discovery and development of novel cancer therapeutics and diagnostics for the benefit of patients.

The consortium aligns four major academic institutions in a unified partnership with the shared goal of creating high-impact research programs to discover new treatments for cancer. The magnitude of the multi-institutional consortium and agreements between Celgene Corporation (NASDAQ: CELG) and each institution will support the rapid delivery of disease-altering programs to the clinic that may ultimately benefit cancer patients, global healthcare systems and society.
Subsequent to establishing the consortium, Celgene entered into four public-private collaboration agreements in which it paid a total of $50 million, $12.5 million to each institution, for the option to enter into future agreements to develop and commercialize novel cancer therapeutics arising from the consortium’s efforts. Over the next ten years the institutions intend to present multiple high-impact research programs to Celgene with the goal of developing new life-saving therapeutics. Subject to Celgene’s decision to opt-in and license the resulting technologies, each program has the potential to be valued at hundreds of millions of dollars.
The four cancer center directors, Steven Burakoff, M.D., of the Icahn School of Medicine at Mount Sinai, Stephen G. Emerson, M.D., Ph.D., of Columbia University, William Nelson, M.D., Ph.D., of Johns Hopkins University and Chi Van Dang, M.D., Ph.D., of the University of Pennsylvania, said in a shared statement, “The active and coordinated engagement, creative thinking and unique perspectives and expertise of each institution have made this collaboration a reality. Our shared vision and unified approach to biomedical research, discovery and development, combined with Celgene’s vast research, development and global commercial expertise, will enable us to accelerate the development and delivery of next-generation cancer therapies to patients worldwide.”

In addition to the benefits of long-standing professional relationships among the four cancer center directors, the depth and breadth of the institutions’ combined research and clinical infrastructures provide an exceptional foundation upon which to build this transformative collaboration. The four institutions collectively care for more than 30,000 new cancer patients each year, and have nearly 800 faculty members who are active in basic and clinical research, and clinical care.

“This is a paradigm-shifting collaboration that further strengthens our innovative ecosystem,” said Bob Hugin, Executive Chairman of Celgene Corporation. “We remain firmly committed to driving critical advances in cancer and believe the tremendous expertise of our collaboration partner institutions will be invaluable in identifying new therapies for cancer patients.”
The four consortium members are among the 69 institutions designated as Cancer Centers by the National Cancer Institute (NCI). These 69 institutions serve as the backbone of NCI’s research in the war against cancer.
The Cancer Trust, a non-profit organization, brought together the four institutions, thereby establishing the multi-institutional research consortium. T.R. Winston & Company, LLC served as the strategic advisor to The Cancer Trust and facilitated negotiations among The Cancer Trust, the institutions and Celgene. The commercialization offices of the four institutions, Columbia Technology Ventures, Johns Hopkins Technology Ventures, Mount Sinai Innovation Partners and the Penn Center for Innovation, subsequently collaborated with Celgene to accelerate this effort to discover and develop new therapies for the treatment of cancer.

“We are extremely proud of what we’ve collectively accomplished through establishing this collaboration and aligning all participants,” said Erik Lium, Ph.D., Senior Vice President of Mount Sinai Innovation Partners. “We look forward to continuing to work closely with one another, our colleagues in research and clinical care, and now with Celgene to advance the discovery of new therapies that will dramatically improve the lives of patients worldwide.”

Body’s Own Gene Editing System Generates Leukemia Stem Cells

Cancer stem cells are like zombies — even after a tumor is destroyed, they can keep coming back. These cells have an unlimited capacity to regenerate themselves, making more cancer stem cells and more tumors. Researchers at University of California San Diego School of Medicine have now unraveled how pre-leukemic white blood cell precursors become leukemia stem cells. The study, published June 9 in Cell Stem Cell, used human cells to define the RNA editing enzyme ADAR1’s role in leukemia, and find a way to stop it.

While DNA is like the architect’s blueprint for a cell, RNA is the like the engineer’s interpretation of the blueprint. That RNA version is frequently flawed in cancer. While many studies have uncovered pivotal DNA mutations in cancer, few have addressed the roles of RNA and mechanisms that regulate RNA.

“In this study, we showed that cancer stem cells co-opt a RNA editing system to clone themselves. What’s more, we found a method to dial it down,” said senior author Catriona Jamieson, MD, PhD, associate professor of medicine and chief of the Division of Regenerative Medicine at UC San Diego School of Medicine.

The enzyme at the center of this study, ADAR1, can edit the sequence of microRNAs, small pieces of genetic material. By swapping out just one microRNA building block for another, ADAR1 alters the carefully orchestrated system cells use to control which genes are turned on or off at which times.

ADAR1 is known to promote cancer progression and resistance to therapy. In this study, Jamieson’s team used human blast crisis chronic myeloid leukemia cells in the lab, and mice transplanted with these cells, to determine ADAR1’s role in governing leukemia stem cells.

The researchers uncovered a series of molecular events. First, white blood cells with a leukemia-promoting gene mutation become more sensitive to signs of inflammation. That inflammatory response activates ADAR1. Then, hyper-ADAR1 editing slows down the microRNAs known as let-7. Ultimately, this activity increases cellular regeneration, or self-renewal, turning white blood cell precursors into leukemia stem cells. Leukemia stem cells promote an aggressive, therapy-resistant form of the disease called blast crisis.

“This is the first mechanistic link between pro-cancer inflammatory signals and RNA editing-driven reprogramming of precursor cells into leukemia stem cells,” said Jamieson, who is also deputy director of the Sanford Stem Cell Clinical Center at UC San Diego Health, director of the CIRM Alpha Stem Cell Clinic at UC San Diego School of Medicine and director of stem cell research at UC San Diego Moores Cancer Center.

After learning how the ADAR1 system works, Jamieson’s team looked for a way to stop it. By inhibiting sensitivity to inflammation or inhibiting ADAR1 with a small molecule tool compound, the researchers were able to counter ADAR1’s effect on leukemia stem cell self-renewal and restore let-7. Self-renewal of blast crisis chronic myeloid leukemia cells was reduced by approximately 40 percent when treated with the small molecule, called 8-Aza, as compared to untreated cells.

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed,” Jamieson said.

Restoring Chemotherapy Sensitivity by Boosting MicroRNA Levels

By increasing the level of a specific microRNA (miRNA) molecule, researchers have for the first time restored chemotherapy sensitivity in vitro to a line of human pancreatic cancer cells that had developed resistance to a common treatment drug.

If the miRNA molecules can be delivered to cells in the human body – potentially with nanoparticles – the technique might one day be used to battle the chemotherapy resistance that often develops during cancer treatment. A research team at the Georgia Institute of Technology identified the miRNA used in the research with a computer algorithm that compared the ability of different miRNAs to control the more than 500 genes that were up-regulated in drug-resistant cancer cells.

The study was scheduled to be reported May 27 in the Nature Publishing Group journal Cancer Gene Therapy.

“We were specifically interested in what role miRNAs might play in developing drug resistance in these cancer cells,” said John McDonald, a professor in Georgia Tech’s School of Biology and director of its Integrated Cancer Research Center. “By increasing the levels of the miRNA governing the suite of genes we identified, we increased the cells’ drug sensitivity back to what the baseline had been, essentially undoing the resistance. This would suggest that for patients developing chemotherapy resistance, we might one day be able to use miRNAs to restore the sensitivity of the cancer cells to the drugs.”

MicroRNAs are small non-coding molecules that function in RNA silencing and post-transcriptional regulation of gene expression. The miRNAs operate via base-pairing with complementary sequences within messenger RNA (mRNA) molecules, silencing the mRNA molecules that control the expression of certain proteins.

Roman Mezencev, a senior research scientist in the McDonald lab, began by exposing a line of pancreatic cancer cells (BxPC3) to increasing levels of the chemotherapy drug cisplatin. After each in vitro treatment, surviving cells were allowed to proliferate before being exposed to a higher level of the drug. After approximately a year and 20 treatment cycles, the resulting cell line had a resistance to cisplatin that was 15 times greater than that of the original cancer cells.

The next step was to study the genetic changes associated with the resistance, comparing levels of more than 2,000 miRNAs in the cisplatin-resistant line to the original cell line that had not been exposed to the drug. Using a hidden Markov model (HMM) algorithm, they found 57 miRNAs that were either up-regulated or down-regulated, and identified miR-374b as the molecule most likely to be controlling the genes that govern chemotherapy resistance.

While previous work by other researchers has shown that miRNAs can provide a mechanism for the development of drug resistance, the Georgia Tech team took the findings a step farther by increasing the expression of miR-374b. When they did, they found that the cells previously resistant to the cisplatin were again sensitive to the drug – almost back to their original levels.

Techniques to control protein expression are already being used in cancer therapy, but McDonald believes there may be benefits in targeting the activity higher up in the process – at the RNA level. Studies by the Georgia Tech team and by other researchers clearly show an association between chemotherapy resistance and changes in levels of certain miRNAs.

“Molecular evolution is a highly efficient process,” McDonald said. “Our evidence suggests that many of the genes regulated by a single microRNA are involved in coordinated cellular functions – in this case, drug resistance. We believe that microRNAs might be particularly good cancer therapeutic agents because when we manipulate them, we are manipulating suites of functionally coordinated genes.”

A next step will be to study the effects of manipulating miRNA levels in animal cancer models. The McDonald research team is currently pursuing this possibility by inserting the microRNAs into tumors using nanoscale hydrogels developed by Andrew Lyon, former chair of Georgia Tech’s School of Chemistry and Biochemistry.

McDonald says the study confirms the role of miR-374b in creating resistance, though he says there could be other microRNA molecules involved, as well.

“These cells have acquired resistance to the drug, and we have found a microRNA that seems to be playing a major role,” he said. “We have shown that we can bring sensitivity to drugs back by restoring levels of miR374b, but there may be other miRNAs that will work equally as well. Just as there are multiple pathways to establish cancer and chemoresistance, there may be multiple pathways to restore chemosensitivity, as well.”

If cancer could one day be treated using miRNAs, it’s likely to be a continuing battle rather than a decisive victory, McDonald said. Cancer cells are very resourceful, and will likely find a new genetic route to resistance if one pathway is destroyed. That could require use of a different miRNA to reverse resistance.

While the miRNA research isn’t likely to provide a “magic bullet” for cancer, it does show the possible role of these tiny RNA molecules in controlling a broad class of bodily processes.

“There is growing evidence that this class of small regulatory RNAs may be involved in many processes ranging from evolution to heart disease,” he said. “MiRNAs are emerging as important players in cancer in general. Here, we are focusing on just one particular aspect of it.”