# Gene therapy for tuberous sclerosis

> **NIH NIH R61** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $420,000

## Abstract

Our team will evaluate the potential for gene therapy to reduce life threatening symptoms in tuberous sclerosis
complex (TSC), which affects 2 million people world-wide. TSC is an autosomal dominant, tumor suppressor
disorder caused by an inherited mutation in either TSC1 (encoding hamartin) or TSC2 (encoding tuberin) with
somatic loss of the corresponding normal allele leading to hamartomas (focal cell overgrowths) in different
organs. Neurological involvement includes cortical tubers, subependymal nodules and subependymal giant cell
astrocytomas with hydrocephalus epilepsy, autism, cognitive impairment and mental health issues. We have
created a stochastic central nervous system (CNS) mouse model of TSC2 which manifests subependymal
overgrowths, hydrocephalus and early death, reflecting what happens in TSC patients. Current standards-of-
care for subependymal lesions in the brain involve neurosurgical craniotomy and/or long term treatment with
rapamycin, both having potentially damaging effects on brain development. Our thesis is that a life-threatening
complication of TSC – hydrocephalus can be prevented with a less invasive and longer lasting procedure, i.e.
intravenous (IV) delivery of an adeno-associated virus (AAV) vector encoding a replacement protein, without
compromising use of other standards-of-care if needed. IV delivery should achieve “extra copies” of the
replacement gene in peripheral tissues reducing the likelihood of other life threatening hamartomas forming in
the body. We will use our CNS Tsc2 mouse model to evaluate the ability of an AAV vector encoding a
condensed version of tuberin (cTuberin) to reduce the size of ependymal abnormalities and extend lifespan.
R61 Aim 1 - Evaluation of cTuberin protein in culture, including use of induced pluripotent stem cells from
patients differentiated into neural progenitor cells, with cytoxicity and functional assays, Go-no-go: cTuberin
must show at least 50% of tuberin activity in suppression of mTOR activity, and normalization of cell size and
rate of cell proliferation. Aim 2 - Optimize AAV serotype and promoter with AAV-cTuberin in CNS Tsc2 mouse
model and evaluate therapeutic efficacy. Behavior, survival times, neuropathology and whole body pathology
will be monitored, as well as vector distribution and the ability of the vector to target cells in the brain and
peripheral tissues. Go-no-go: AAV-cTuberin must at least double the average lifespan in this CNS Tsc2 model
and show comparable effectiveness to rapamycin (positive control). In R33 Aim 3 - Evaluate dose escalation
and potential toxicity of AAV-cTuberin in Tsc2+/- and CNS Tsc2 mouse models, as well as obtaining
quantitative measurements of ventricular volumes in treated and non-treated mice by magnetic resonance
imaging. Our team of TSC experts includes Drs. Breakefield (preclinical gene therapy for neurologic diseases),
Maguire (AAV vectors), Ramesh (biochemistry and cell biology), Stemmer-Rachamimov (neuroanatomy) and
Thie...

## Key facts

- **NIH application ID:** 9979978
- **Project number:** 5R61NS108232-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** XANDRA OWENS BREAKEFIELD
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979978

## Citation

> US National Institutes of Health, RePORTER application 9979978, Gene therapy for tuberous sclerosis (5R61NS108232-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979978. Licensed CC0.

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