# CRISPR Based Rescue of Glaucoma in Lowe Syndrome

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $613,140

## Abstract

ABSTRACT
Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by bilateral congenital cataracts
and glaucoma, renal tubular dysfunction, and mental retardation. Mutations in OCRL1, an inositol polyphosphate
5-phosphatase, cause Lowe syndrome. Despite the identification of OCRL1 as the causal gene underlying this
rare disease, there is currently no therapy for Lowe syndrome. Children with Lowe syndrome often go blind due
to glaucomatous optic neuropathy. We have developed a novel CRISPR-based approach to transcriptionally
regulate the inositol enzymes that control the substrate of OCRL. We have developed a nuclease-deficient Cas
protein that allows activation or inactivation of endogenous genes. Our preliminary data shows a novel
hypercompact CasMINI for gene editing in a single viral package that allows “Plug-and-Play” delivery. We also
established a nuclease-deficient CRISPR-CasMINI (dCasMINI) for gene transcriptional activation of protein
expression, with functional rescue in vivo. We also established human Lowe syndrome-based human iPS stem
cells, mouse and zebrafish models, and viral delivery approaches for in vivo therapies. We hypothesize that
CRISPR-Cas based rescue strategies for inositol 5-phosphatases will restore the imbalance due to the loss of
OCRL in Lowe syndrome. Our aims are to (1) transcriptionally activate a compensatory 5-phosphatase that
degrades PI(4,5)P2, (2) generate exon-skipping transcripts to reduce OCRL loss phenotypes in human iPS
models of Lowe syndrome, (3) use CRISPR-Pass strategy with both adenosine base editors and prime editors
to correct OCRL gene mutations in Lowe patient derived cells. We anticipate this work will provide critical insights
into how CRISPR-Cas can be used to rescue the loss of OCRL and provide important translation approaches
for Lowe syndrome and then expanded to treat other forms of inherited genetic eye diseases.

## Key facts

- **NIH application ID:** 10883422
- **Project number:** 2R01EY025295-06A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Yang Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,140
- **Award type:** 2
- **Project period:** 2016-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883422

## Citation

> US National Institutes of Health, RePORTER application 10883422, CRISPR Based Rescue of Glaucoma in Lowe Syndrome (2R01EY025295-06A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10883422. Licensed CC0.

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