There’s some good news for a company and a therapeutic approach that CIRM has been supporting for many years.
In September 2018, CRISPR Theraputics and ViaCyte entered a partnership to discover, develop and market gene-edited stem cell-derived therapies to treat type 1 diabetes (T1D). Today, they may stand one step closer to their goal.
Last week the companies jointly announced that they have dosed the first subject in the Phase 1 clinical trial of VCTX210 for the treatment of T1D. VCTX210 is an investigational stem cell-based therapy. It was developed combining CRISPR’s gene-editing technology with ViaCyte’s stem cell expertise to generate pancreatic beta cells that can evade the immune system.
ViaCyte, a regenerative medicine company long backed by CIRM, has developed an implantable device which contains pancreatic endoderm cells that mature over a few months and turn into insulin-producing pancreatic islet cells, the kind destroyed by T1D.
ViaCyte’s implantable stem cell pouch
Using CRISPR technology, the genetic code of the implanted cells is modified to create beta cells that avoid all recognition by the immune system. This collaboration aims to eliminate the requirement of patients taking daily immunosuppressants to stop the immune system from attacking the implanted cells.
The first phase of the VCTX210 clinical trial will assess the safety, tolerability, and immune evasion in patients with T1D.
“We are excited to work with CRISPR Therapeutics and ViaCyte to carry out this historic, first-in-human transplant of gene-edited, stem cell-derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression,” said James Shapiro, a clinical investigator in the trial. “If this approach is successful, it will be a transformative treatment for patients with all insulin-requiring forms of diabetes.”
As someone with a family history of type 1 diabetes (T1D) I know how devastating the condition can be. I also know how challenging it can be to keep it under control and the consequences of failing to do that. Not maintaining healthy blood sugar levels can have a serious impact on the heart, kidney, eyes, nerves, and blood vessels. It can even be fatal.
Right now, controlling T1D means being careful about what you eat, when you eat and how much you eat. It also means regularly checking your blood throughout the day to see if the glucose level is too high or too low. If it’s too high you need to inject insulin; if it’s too low you need to take a fast-acting carbohydrate such as fruit juice or glucose to try and restore it to a healthy level.
That’s why two new approaches to T1D that CIRM has supported are so exciting. They both use small devices implanted under the skin that contain stem cells. The cells can both monitor blood sugar and, if it’s too high, secrete insulin to bring it down.
We sat down with two key members of the Encellin and ViaCyte teams, Dr. Crystal Nyitray and Dr. Manasi Jaiman, to talk about their research, how it works, and what it could mean for people with T1D. That’s in the latest episode of our podcast ‘Talking ‘Bout (re)Generation’.
I think you are going to enjoy it.
This is the size of the implant that ViaCyte is using.This is the size of the implant Encellin is using
Dr. Crystal Nyitray, CEO & Co-founder Encellin
Dr. Manasi Jaiman, Vice President, Clinical Development ViaCyte
This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.
Rare Disease
Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2.
Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.
However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.
Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains.
In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,
“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”
Type 1 Diabetes
Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.
The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.
“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”
Heart Function
Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.
In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.
In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,
“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”
The full results of this study were published in Nature Genetics.
Dr. Peter Stock at the capitol in Sacramento in May 2016. Photo courtesy of Steve German.
Today the governing Board of the California Institute for
Regenerative Medicine (CIRM) awarded $11.08 Million to Dr. Peter Stock at the
University of California San Francisco (UCSF) to conduct a clinical trial for
treatment of Type 1 Diabetes (T1D).
The
award brings the total number of CIRM funded clinical trials to 54.
T1D is a chronic autoimmune disease that affects
approximately 1.25 million Americans, with 40,000 new diagnoses each year. T1D occurs as a result of the body’s immune
system destroying its own pancreatic beta cells. These cells are necessary to produce the
vital hormone insulin, which regulates blood sugar levels in the body. As a result of a lack of insulin, there is no
blood sugar control in T1D patients, gradually causing disabling and
life-threatening complications such as heart disease, nerve damage, and vision
problems.
There is no cure for T1D.
Current treatments consist of blood sugar monitoring and multiple daily
injections of insulin. Transplantation of
beta cells, contained in donor pancreatic islets, can reverse the symptoms of
diabetes. However, due to a poor islet survival
rate, transplants require islets from multiple donors. Furthermore, since islet cells are
transplanted directly into the vessels that enter the liver, it is extremely
difficult to monitor and retrieve these cells should the need arise.
Dr. Stock’s clinical trial at UCSF aims to address these
limitations. The trial will be using parathyroid
glands to aid in the success and viability of the transplant procedure. Co-transplantation of islets and parathyroid
glands, from the same donor, substantially increases beta cell survival, potentially
enabling adequate long-term insulin production and removing the need for
multiple donors. Additionally, the
co-transplantation will occur in the patient’s forearm, which allows for easier
monitoring and improves the effectiveness and accessibility of islet
transplants for patients.
“This team’s innovative approach to develop a definitive
cell-based treatment for Type 1 Diabetes has the potential to address an unmet
medical need that exists despite advancements in diabetes therapy.” says
Maria T. Millan, M.D., the President and CEO of CIRM. “The success of this clinical trial could
enable the successful application of islet cell transplants but also of future stem-cell
based approaches for diabetes.”
CIRM has funded three other clinical trials for T1D. One of these was conducted by Caladrius Biosciences and two by ViaCyte, Inc.
Matthias Hebrok, PhD, senior author of new study that transformed human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.
More often than not, people don’t really think about their blood sugar levels before sitting down to enjoy a delicious meal, partake in a tasty dessert, or go out for a bicycle ride. But for type 1 diabetes (T1D) patients, every minute and every action revolves around the readout from a glucose meter, a device used to measure blood sugar levels.
Normally, the pancreas contains beta cells that produce insulin in order to maintain blood sugar levels in the normal range. Unfortunately, those with T1D have an immune system that destroys their own beta cells, thereby decreasing or preventing the production of insulin and in turn the regulation of blood sugar levels. Chronic spikes in blood sugar levels can lead to blindness, nerve damage, kidney failure, heart disease, stroke, and even death.
Those with T1D manage their condition by injecting themselves with insulin anywhere from two to four times a day. A light workout, slight change in diet, or even an exciting event can have a serious impact that requires a glucose meter check and an insulin injection.
There are clinical trials involving transplants of pancreatic “islets”, clusters of cells containing healthy beta cells, but these rely on pancreases from deceased donors and taking immune suppressing drugs for life.
But what if there was a way to produce healthy beta cells in a lab without the need of a transplant?
Dr. Matthias Hebrok, director of the UCSF diabetes center, and Dr. Gopika Nair, postdoctoral fellow, have discovered how to transform human stem cells into healthy, insulin producing beta cells.
In a news release written by Dr. Nicholas Weiler of UCSF, Dr. Hebrok is quoted as saying “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”
For the longest time, scientists could only produce cells at an immature stage that were unable to respond to blood sugar levels and secrete insulin properly. Dr. Hebrok and Dr. Nair discovered that mimicking the “islet” formation of cells in the pancreas helped the cells mature. These cells were then transplanted into mice and found that they were fully functional, producing insulin and responding to changes blood sugar levels.
Dr. Hebrok’s team is already in collaboration with various colleagues to make these cells transplantable into patients.
Gopika Nair, PhD, postdoctoral fellow that led the study for transforming human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.
Dr. Nair in the article is also quoted as saying “Current therapeutics like insulin injections only treat the symptoms of the disease. Our work points to several exciting avenues to finally finding a cure.”
“We’re finally able to move forward on a number of different fronts that were previously closed to us,” Hebrok added. “The possibilities seem endless.”
CIRM has funded three separate human clinical trials for T1D that total approximately $37.8 million in awards. Two of these trials are being conducted by ViaCyte, Inc. and the third trial is being conducted by Caladrius Biosciences.
The Stem Cellar 