In this blog I'm going to report on three different clinical trials involving transplantation. The basic idea for all of these is to transplant beta cells into someone with T1D, and those new beta cells will produce insulin and cure the person. As I describe below, this idea has been around for 40 years, but it has not been successful in the past because of two problems: First, the body's immune system attacks the transplanted cells because it is working properly and they are foreign cells. Second, the body's immune system attacks the new cells because it is broken and mistakenly attacks beta cells. Some people think there is a third problem: beta cell supply, but personally, I'm less worried about that. These three trials all attack these problems in different ways.
VX-880
A lot of people are excited about this trial because it is generating headlines like "Vertex VX-880 Clinical Results Lead To Insulin-Independence". This is not a lie, but it is highly misleading. I discuss the problems with transplants which require immune suppression below (and VX-880 requires immune suppression). However, it is important to understand that these are not recent improvements. Transplantation trials have been getting results like this for a long time.
Another reason people are excited about this study, is because the beta cells used here are created from stem cells, and therefore there is an unlimited supply available, and a lot of control over how they are made. Previous studies used beta cells harvested from cadavers or from pigs, each of which has its own problems of supply.
For over 20 years islet transplantation have led to many people not needing to inject insulin for many years (search for "Edmonton Protocol" with Google). These are the same results seen in VX-880. They are not seen as a cure, because of the bad effects of immune suppression drugs, which are required, and which must be taken for the rest of the person's life, and because they only work for a few years. Typically, people do not need to inject insulin for 5 or 10 years, but then they do again. So headlines reporting on no injecting insulin a year after a transplant are nothing new.
This trial is currently running, but I'm not covering it as a potential cure for T1D. It requires each person to take a full suite of immune suppression drugs to support the transplant. They will need to do this for their whole lives, even if the transplant only works for a few years. Furthermore, the drug combinations used for transplants have significant bad long term side effects, causing health problems in their own right.
Therefore, I view transplants that require life long immune suppression to be trading one drug treatment (T1D) for another (Immune Suppression), and not a cure. At this point, I'm not even sure which is more dangerous, more hassle, and has more side effects.
Of course, in medicine, things change over time. In the future immune suppression may become easier and safer and I might revisit this decision, but until then, for me transplants requiring immune suppression are not cures.
Clinical Trial Record: https://www.clinicaltrials.gov/study/NCT04786262
VX-264 (Phase-I)
For me, VX-264 is much more interesting than VX-880, even though they both use the same cells, because it does not require life long immune suppression. In VX-264, the islet cells are encapsulated in a special, high tech membrane. The membrane allows nutrients and sugars in, and wastes and insulin out, but blocks immune cells. This is possible because nutrients, sugar, waste, and insulin are all relatively small, while immune cells are relatively large.
This study will enroll 17 adults and everyone will get the treatment (no control group), so I consider this a phase-I trial. Everyone will have established T1D for at least 5 years.
The outcomes of this trial are a little complex. Early in the study they will focus on adverse events (side effects) for a total of 2 years after the transplants, but later they focus on C-peptides 3 months after the transplants. The secondary endpoints include C-peptides, insulin use, and A1c numbers for 2 years after transplant.
They expect to finish in mid 2026.
If successful, this would allow islet transplantation without immune suppression, and that would be a cure for T1D.
They are recruiting at several locations in the US and Europe. You can contact them at medicalinfo@vrtx.com or 617-341-6777, or look in the Trial Page or the "Contacts and Locations" section of the clinical trial record, which has an interactive map of the study locations.
Trial Page: https://clinicaltrials.vrtx.com/safety-tolerability-and-efficacy-study-vx-264-participants-type-1-diabetes
DiaTribe Article: https://diatribe.org/join-type-1-diabetes-trial-testing-encapsulated-insulin-producing-cells
News Article: https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-fda-clearance-investigational-new-drug
Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05791201
Discussion
This idea of filtering out immune cells, but letting the smaller stuff in and out of the islet has a long history. Research had already started in the 1980s, and the earliest clinical trials were running in the 1990s. Obviously, none of those were successful, which suggests to me that the idea is a lot easier to think of than to actually implement. The English language idiom is "The devil is in the details." I'm not sure how many transplantation with high tech membrane type clinical trials have been run in the last 30 years, maybe 5 or 10, but certainly none was successful, so it is a hard problem that Vertex is trying to solve.
VCTX211 (Phase-I)
The VCTX211 clinical trial is also avoiding life long immune suppression. It is being run by CRISPR Therapeutics AG, and combines technology from them with stem cells and encapsulation technology from ViaCyte (since bought by Vertex). CRISPR is powerful gene editing technology which is too complex for me to discuss here, so I don't, but you can see a list of all the different things they hope to do with it, here: https://crisprtx.com/pipeline.
This trial uses the CRISPR gene editing technique to modify the implanted cells so they are invisible to the immune system. Therefore, they do not trigger the natural immune system rejection of transplanted organs, nor can the autoimmune attack which triggers T1D affect them. No long-term immune suppression drugs are required.
ViaCyte is part of a line of companies that has been trying a transplantation cure since the 1990s, the historical line is Neocrin -> Novocell -> ViaCyte -> Vertex.
This study will enroll 40 adults who have had T1D for 5 years or longer. They will be followed for 1 year. Everyone will get the treatment; there is no control group. The primary end points include side effects and C-peptide generation. Secondary end points include several of insulin, A1c, and side effect measurements.
They expect to finish in mid 2025.
This trial is recruiting in two locations in Canada: Edmonton and Vancouver. You can contact them at +1-877-214-4634 or MedicalAffairs@crisprtx.com.
Clinical Trial Registry: https://www.clinicaltrials.gov/study/NCT05565248
Discussion
This study is absolutely huge, both for T1D and for every other transplantation cure in the world. Right now, most organ transplantation is a big deal, because it requires immune suppression, which has a whole raft of problems and issues associated with it. If CRISPR can be used to avoid that, suddenly every form of transplantation is going to become a much better, much more common cure than it was before.
The idea that using CRISPR to make stem cells that could be transplanted to anyone has been an active area of research for years now, and here is an article that covers it from 2019:
https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system
Although I don't believe that this research was exactly the same as what is being tested in VCTX211.
Recent news on CRISPR based treatments of sickle cell disease:
https://www.statnews.com/2023/12/08/fda-approves-casgevy-crispr-based-medicine-for-treatment-of-sickle-cell-disease/
But it is important to note that for this disease, CRISPR is not used to make the cells invisible to the immunological system. That is why the VCTX211 clinical trial is so important.
