# Reverse transcriptase inhibition as a novel therapeutic approach for ADAR-1-related Aicardi Goutières Syndrome

> **NIH NIH R21** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $499,550

## Abstract

Aicardi Goutières Syndrome (AGS) is an autoinflammatory leukodystrophy that results in severe neurologic
disability along with systemic complications. AGS is caused by mutations in genes associated with DNA/RNA
processing or intracellular sensing, leading to increased interferon response. While typically elicited due to a viral
infection, in AGS these immune responses are triggered due to accumulation of endogenous nucleic acids such
as retroelements. Retroelements, particularly LINE-1 is implicated in AGS caused due to mutations in TREX1,
SAMHD1, RNASEH2A/B/C. But this association is not understood for mutations in the AGS genes IFIH1 and
ADAR1. A prior pilot study shows that administration of reverse transcriptase inhibitor (RTI) can inhibit
retroelement accumulation, decreasing activation of IFN pathways in AGS patients with TREX1, SAMHD1,
RNASEH2A/B/C mutations. A follow-up clinical trial is being conducted at Children’s Hospital of Philadelphia
(CHOP) as part of the Leukodystrophy Center of Excellence for the same patient population. However, ADAR1
patients (~14% of AGS patients) will be excluded from this study, as there is no evidence showing ADAR1
mutation leads to dysregulation of retroelements. This proposal will address this critical gap using human induced
pluripotent stem cells (iPSC) derived from ADAR1 patients as a novel and relevant model system. Specifically,
we will determine if ADAR1 mutations result in the dysregulation and accumulation of LINE-1 and Alu
retroelements, which contributes to IFN-mediated cellular pathology in AGS (Aim1). We will further explore if
treatment with RTI will be beneficial for ADAR1 mutation as observed for the other genotypes (Aim2) using
molecular, biochemical and longitudinal survival assays. Our preliminary data show promising results and overall
this proposal will combine our expertise in neuroscience and innate immunity to help shed light on the
fundamental biology of a rare inherited leukodystrophy. The knowledge to be gained is also highly translational
and immediately applicable to inclusion criteria for enrollment of AGS patients in the ongoing clinical trials at
CHOP.

## Key facts

- **NIH application ID:** 10288270
- **Project number:** 1R21NS123477-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Adeline Lucie Vanderver
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $499,550
- **Award type:** 1
- **Project period:** 2022-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288270

## Citation

> US National Institutes of Health, RePORTER application 10288270, Reverse transcriptase inhibition as a novel therapeutic approach for ADAR-1-related Aicardi Goutières Syndrome (1R21NS123477-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10288270. Licensed CC0.

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