# Manipulating DNA Damage-response Signaling for the Treatment of Type 1 Diabetes

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $446,790

## Abstract

Abstract
Type 1 diabetes (T1D) is a common autoimmune disease in children and young adults. T1D presents
as acute onset hyperglycemia resulting from the immune-mediated destruction of insulin-producing pancreatic
beta cells. The central pathogenic driver of T1D is the beta cell antigen-specific (ag.-sp.) T cell. There is no durable
cure for T1D; the sole and costly treatment for T1D remains daily insulin replacement. Even with vigilant glucose
monitoring and control, T1D patients still suffer a host of life-threatening sequalae including macro- and micro-
vasculopathies, neuropathy, nephropathy, amputations, stroke, and blindness. While progress has been made in
(i) producing and delivering insulin, (ii) monitoring blood glucose, (iii) identifying autoantigens, (iv) defining
genetic risk factors, (v) understanding underlying immune dysfunction, and (vi) producing and harvesting
pancreatic islet cells for transplant, the most intractable barrier remains our inability to remove or control islet
ag.-sp. T cells, without which the promise of preventing/curing T1D will likely fail.
To surmount this critical barrier, we devised the means to eliminate diabetogenic T cells from
the adaptive immune repertoire. In fact, when applied to non-obese diabetic (NOD) mice with spontaneous
new-onset T1D, we observe (i) a striking prolongation of the remission or “honeymoon” period, (ii) a significant
reduction in beta cell-specific CD4+ and CD8+ T cells, (iii) a significant preservation of beta cells, and (iv) a highly
significant reduction (78%) in the number of NOD mice that transit to overt diabetes.
The premise: As T cells toggle between distinct states – naïve, activated effector, quiescent and activated
memory – they exhibit ineluctable properties that we can precisely target. This is particularly true of activated
effector CD4+ and CD8+ T cells (Teff). Unlike their counterparts, Teff cells divide rapidly – at a rate of once every
5-6 hours in vivo – and exhibit an intrinsic DNA damage response (DDR) that places them on the edge of
apoptotic cell death. We hypothesize (i) that this unique aspect of lymphocyte biology lead to genomic stress
in acutely activated lymphocytes and (ii) that manipulation of DDR signaling pathways allows for selective
therapeutic targeting of pathological T cells. Consistent with these hypotheses, we find that both mouse and
human Teff cells display a pronounced DDR, as evidenced by DNA damage, phospho-ser139 H2AX (γH2AX),
and phosphorylation of ATM, CHK2, and p53. Moreover, we find that novel drugs that potentiate p53 (via
inhibition of MDM2) or impair cell cycle checkpoints (via inhibition of CHK1/2 or WEE1) lead to the selective
elimination of pathological Teff cells in vivo when given during a prescribed therapeutic window. In combination
of these compounds – which we termed “p53 potentiation with checkpoint abrogation” (PPCA) – display clear
therapeutic benefit, targeting pathological T cells but does not naive, regulatory, or...

## Key facts

- **NIH application ID:** 9878103
- **Project number:** 5R01DK117632-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** JONATHAN David KATZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,790
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878103

## Citation

> US National Institutes of Health, RePORTER application 9878103, Manipulating DNA Damage-response Signaling for the Treatment of Type 1 Diabetes (5R01DK117632-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878103. Licensed CC0.

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