Don’t you just love living in the future? It isn’t only diabetes where biological and medical sciences are leaping ahead pretty much every week. Cancers of many kinds, heart disease, kidney disease, infectious diseases...Now we can make Beta cells that produce insulin from ordinary pancreatic alpha cells, with the help of a suitable modified virus. If it pans out and can eventually get FDA approval, then as soon as one or another possible treatment for neuropathy also pans out, we can say goodby to most of the scourge of diabetes worldwide. Well, also if we can get up the political will to fund it, something we are at last ready to discuss around the world.
Abstract Title: Immune Modulation Sustains Alpha Cell Reprogramming and Mitigates Immune Responses to AAV in a Diabetic Non-Human Primate Model
Session Title: Challenges in Immunological Responses to Therapeutic Interventions
Presenter: Hannah Rinehardt, MD, University of Pittsburgh Medical Center
Presentation Date: May 16, 2025
Don’t worry about all the tech jargon. A modified virus inserts genes into alpha cells to turn them into insulin-producing beta cells. This would benefit sufferers from both Type 1 and Type 2 diabetes. The rest of the tech is about how to go about it all, and how to overcome various biological obstacles.
IOW, it’s another frabjous day in diabetes research, even if this doesn’t directly become an approved treatment.
Abstract to be presented for oral presentation at the ASGCT 28th Annual Meeting:
Gene therapy using recombinant adeno-associated virus (rAAV) offers a promising opportunity for curative therapy in diabetes mellitus. Retrograde intraductal infusion of rAAV6 to deliver Pdx1 and MafA, converting alpha cells into beta-like cells that secrete insulin physiologically, reverses diabetes in mouse models. Little is known about the direct infusion of AAV into the pancreatic duct for gene therapy in non-human primates (NHPs). In clinical trials, anti-viral immunity to AAV can be a barrier to successful gene therapy. Researchers evaluated the immune response to direct infusion of rAAV into the pancreatic duct of NHPs with streptozotocin-induced diabetes and evaluated how to best manage immune responses.
Diabetes was induced with streptozotocin (STZ) in cynomolgus macaques. NHPs received retrograde intraductal infusion of rAAV via laparotomy for precise delivery to the pancreas. rAAV capsids were chosen based on tropism for endocrine cells, and pre-existing neutralizing antibody titers (NAbs) were negative. Blood work including serum C peptide and IV glucose tolerance tests were serially obtained to monitor therapeutic efficacy. Immune response monitoring was performed for up to 4 months post-infusion and included serial NAbs, ELISpot assays, and immunophenotyping. Pancreatic tissues were analyzed using IHC and RNA-scope for beta cell markers, as well as single-cell RNA transcriptomics.
One-month post-infusion, NHPs showed improved glucose tolerance and reduced insulin requirements. The AAV6 capsid with endocrine-specific promoters driving Pdx1 and MafA showed durable effects. ELISpot-positive cytotoxic T cells and neutralizing antibodies developed when steroids were absent. With steroid-sparing regimens, pancreatic B and T lymphocyte populations were noted on scRNA sequencing. Temporary immunosuppression (IS), using a combination of rituximab, rapamycin, and steroids, for a 3-month course is largely effective at preventing anti-viral immunity. Despite complete IS discontinuation at 3 months post-infusion, meaningful anti-viral immune response was not mounted up to one month after IS withdrawal as evidenced by low NAb titers and negative ELISpot analysis. Additionally, rAAV gene therapy in these animals remained effective and glucose tolerance continued improving in the absence of immunosuppression.
In conclusion, researchers developed a novel rAAV gene therapy approach and demonstrated that infusion of rAAV directly into the pancreatic duct of NHPs induces an anti-viral immune response. The anti-viral immune response in NHPs can be largely prevented by administration of a multi-agent IS and can allow for sustained therapeutic effects.
About GPX-002
GPX-002, which has been exclusively licensed from the University of Pittsburgh, is currently being developed using the same construct for the treatment of both Type 1 diabetes (T1D) and Type 2 diabetes (T2D). The same general novel approach is used in each of T1D and T2D whereby an adeno-associated virus (AAV) vector containing the Pdx1 and MafA genes is administered directly into the pancreatic duct. In humans, this can be done with a routine endoscopy procedure. In T1D, GPX-002 is designed to work by transforming alpha cells in the pancreas into functional beta-like cells, which can produce insulin but may be distinct enough from beta cells to evade the body's immune system. In vivo, preclinical studies show that GPX-002 restored normal blood glucose levels for an extended period of time in T1D mouse models. In T2D, where autoimmunity is not at play, GPX-002 is believed to rejuvenate and replenish exhausted beta cells.
Meanwhile
The New Yorker [paywalled]: A Life-Changing Scientific Study Ended by the Trump Administration
Robert F. Kennedy, Jr., declared chronic diseases an “existential threat.” Then his agency terminated one of the world’s longest-running diabetes trials.
Trump Administration Cancels Crucial Funding for Diabetes Prevention Program
- The NIH's funding cancellation for the DPP is linked to the Trump administration's actions against Columbia University.
- The DPP showed a 58% reduction in type 2 diabetes risk through lifestyle changes, with metformin reducing risk by 31%.
Feh.
I can’t take metformin, which gives me horrible duiarrhea,
