# Endogenous alpha-to-beta cell transdifferentiation in diabetes

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $374,150

## Abstract

PROJECT SUMMARY AND RELEVANCE
An ideal solution to the treatment or cure of diabetes mellitus would be the formation of new functioning
β-cells from the patient’s own tissues, thereby avoiding the need for transplant immunosuppression.
Abundant recent data has suggested that α-cells are a likely source for endogenous transdifferentiation
into β-cells. Here, we describe a pancreatic intraductal viral delivery system in the mouse, where a single
infusion of an adeno-associated virus (AAV) carrying a pdx1/mafA expression vector in a diabetic mouse
can induce robust and durable α-cell transdifferentiation into β-cells through neogenesis, with recovery of
over 60% of the β-cell mass within 4 weeks and persistent, indefinite euglycemia. Serendipitously, when
this β-cell neogenesis was induced in NOD mice, the mice became euglycemic for 4 months or more,
without any additional therapy or immunosuppression. To our knowledge no clinically applicable β-cell
replacement therapy in NOD mice has been successful without immunosuppression. We suspect that the
neogenic β-cells may not be rejected because they are “imperfect” β-cells by RNA-seq analysis. Since
pancreatic duct injection is routinely performed in humans as a relatively simple, non-surgical procedure,
and since numerous viral gene therapy trials are currently ongoing for several diseases, we feel that our
approach may be rapidly translatable to humans with diabetes mellitus, potentially both type 1 and type 2.
In this proposal we will first better delineate the phenotype of these neogenic mouse β-cells derived from
α-cells in terms of function and resistance to stressors that normally can cause β-cell death. We will then
strive to better understand how they form, their proliferative capacity, RNA expression and gene
methylation profile. We will then study ways to optimize their formation through promoter work for the
virus construct, and to better understand ways that anti-AAV neutralizing antibodies may affect the
effectiveness of this gene therapy approach. Next, we will pursue the feasibility of a novel lipid
nanoparticle technology to replace the need for AAV in the induction of α-to-β-cell transdifferentiation.
Since glucagon has been shown to play an important role in α-to-β-cell transdifferentiation, we will study
its role in this system. We will study the potential therapeutic effect of such α-to-β-cell
transdifferentiation in models of type 2 diabetes mellitus. Lastly, we will investigate the function of
human islets that have undergone α-to-β-cell transdifferentiation, both in vitro and in vivo. In summary,
we feel that the proposed studies, if successful, should position us well in preparation for clinical trials in
humans with diabetes.

## Key facts

- **NIH application ID:** 9899977
- **Project number:** 5R01DK112836-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** GEORGE K. GITTES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $374,150
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899977

## Citation

> US National Institutes of Health, RePORTER application 9899977, Endogenous alpha-to-beta cell transdifferentiation in diabetes (5R01DK112836-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9899977. Licensed CC0.

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