# Gene Therapy Rescue of Angelman Syndrome with Reelin

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $411,125

## Abstract

Abstract: Angelman syndrome (AS) is a genetic disorder occurring approximately one in every 15,000 births.
It is characterized by severe intellectual disability, seizures, difficulty speaking and ataxia. The gene responsible
for AS was identified as UBE3A and encodes for E6AP, an E3 ubiquitin ligase. A unique feature of this gene is
that it undergoes maternal gene imprinting in a neuron-specific manner. In the majority of AS cases, there is a
mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental
disomy or mismethylation of the maternal allele. Currently, the specific molecular mechanisms of E6AP action
that lead to cognitive disruption in AS is not defined and this has likely contributed to lack of therapeutics.
 It has been shown in AS patients and the AS mouse, that the extracellular matrix protein Reelin (which
modulates nearly all of the molecular components listed above) is significantly reduced. More important to this
study, Reelin supplementation can recover the phenotype of AS mice from a single intracerebroventricular (ICV)
protein injection. However, due to a lack of small molecule agonists for Reelin signaling, there is an absence of
studies exploring effects of long-term increased Reelin signaling as a potential therapeutic for AS. In order to
address this, we generated a novel small active Reelin construct that can be packaged into an adeno-associated
virus (AAV) vector to achieve long-term elevated Reelin signaling within the brain. We demonstrate that this
fragment exhibits the same biological effects as full-length Reelin, as exhibited by behavioral rescue in a mouse
model of Fragile X syndrome (FXS) using both protein and AAV delivery approaches.
 We previously shown that a rAAV Ube3a gene replacement therapy was successful in rescuing some
cognitive impairments in AS mice but did not fully recover long-term potentiation (LTP) deficits or improve motor
deficits. With current viral vectors it is not feasible in humans or even animal models to transduce all neurons
within the brain, which may limit the effectiveness of gene therapy with cellular proteins such as E6AP. Our new
approach offers the distinct advantage of using the secreted Reelin construct, which can diffuse from a subset
of transduced cells to achieve a broader distribution within the brain. We hypothesize this Reelin gene therapy
approach will rescue synaptic plasticity and cognitive deficits in the AS rat. We will test our hypothesis with the
following aims.
 Aim 1: rAAV9-R36 rescues cognitive deficits in AS rats.
 Aim 2: rAAV9-R36 improves electrophysiology deficits in AS rats.
 With therapeutic interventions currently lacking for AS, our unique Reelin analog offers a novel therapeutic
perspective to improve cognition in AS.

## Key facts

- **NIH application ID:** 10317654
- **Project number:** 1R21NS124195-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Kevin Ron Nash
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,125
- **Award type:** 1
- **Project period:** 2021-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317654

## Citation

> US National Institutes of Health, RePORTER application 10317654, Gene Therapy Rescue of Angelman Syndrome with Reelin (1R21NS124195-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10317654. Licensed CC0.

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