# Gene Therapy for Diabetes

> **NIH NIH U01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $720,877

## Abstract

PROJECT SUMMARY
Two potential approaches exist for the replacement of the β-cells lost in type 1 diabetes (T1D). The first is to
transplant new β-cells derived from either allogeneic pancreas donors or stem cells. The second approach is to
generate new β-cells in situ in the T1D patient without any need for cell transplantation. This can be achieved
by transcription factor mediated reprogramming of endodermal cell types related to β-cells. Gene therapy
vectors are used to deliver the reprogramming factors.
 We and others have recently found that it is possible to correct diabetes in mice by retrograde ductal
injection of reprogramming vectors. Intraductal delivery has the advantage of delivering a high dose of gene
therapy vector locally, minimizing systemic side effects and achieving a high local concentration of
reprogramming factors. Furthermore, this route of administration is readily feasible in humans, as ERCP
(endoscopic retrograde cholangio-pancreatography) is a routine procedure in clinical gastroenterology.
 Preclinical work in rodents indicates that α-cells are the prime target for reprogramming, while
pancreatic ducts may also be converted to functional β-like cells.
 In this proposal, we will develop AAV vectors that are optimized for reprogramming the α-cells of
humans and non-human primates to the β-cell fate after intraductal delivery. We are building on the progress
made in our current HIRN UC4 grant, in which we developed novel AAV capsids capable of transducing
human endocrine cells with high efficiency. We also evolved cis-regulatory elements (CREs) capable of
restricting transgene expression to only β-cells.
 In Aim 1, we will produce novel AAV capsids (variants) that are highly efficient in transducing pancreatic
α-cells and duct cells after retrograde injection in non-human primates in vivo. Highly innovative capsid
evolution methods will be used. In Aim 2, we will generate CREs that direct transgene expression specifically
to the reprogramming target, i.e. α-cells. Cell-type specific promoters will be combined with microRNA
recognition elements to achieve this goal. Finally, in Aim 3, AAV capsids generated by Aim 1 and CREs
developed in Aim 2 will be combined to produce optimized AAV capable of delivering reprogramming factors to
α-cells and its capability of reprogramming will be assessed in non-human primates.
 Successful execution of this work will generate the preclinical data needed to determine whether this
approach has potential for clinical application in humans.

## Key facts

- **NIH application ID:** 10239013
- **Project number:** 5U01DK123608-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Markus Grompe
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $720,877
- **Award type:** 5
- **Project period:** 2019-09-20 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239013

## Citation

> US National Institutes of Health, RePORTER application 10239013, Gene Therapy for Diabetes (5U01DK123608-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10239013. Licensed CC0.

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