# Genetic Repair of Familial Hypercholesterolemia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $645,390

## Abstract

PROJECT SUMMARY
Familial hypercholesterolemia is an autosomal dominant disease most often caused by loss of function
mutations in the low density lipoprotein receptor (LDLR). Loss of both LDLR alleles in homozygous FH (HoFH)
results in excessively high levels of plasma cholesterol, xanthomas, premature atherosclerosis, and death in
the first decades of life if untreated. Current treatments are largely ineffective for HoFH and more permanent
solutions are desperately needed. Liver-directed gene therapy using Adeno-Associated Viral (AAV) vectors is
an area of intense research that is very near to achieving meaningful correction of several inherited diseases.
While ongoing clinical trials with AAV are showing promising results, conventional (additive) gene therapy has
limitations including: transgene silencing, imprecise control of expression levels, immune responses to
transgene and capsid protein, and the loss of episomal AAV genomes to cell division. We believe many of
these may be solved by a gene editing approach using the clustered regularly interspaced short palindromic
repeats (CRISPR)-Cas9 system. Our long-term goal is to refine and optimize our AAV-based gene therapy
platform for repair of disease-causing alleles underlying the most severe lipid disorders. The objective of the
current application is to perform preclinical gene therapy to correct the metabolic defect in Familial
Hypercholesterolemia (FH) in a mouse model via AAV-based genome editing. Our central hypothesis is that
AAV-mediated homologous recombination, in combination with CRISPR/Cas9 directed DNA cleavage, can
effectively repair a mutant version of the Ldlr gene with high efficiency. In Aim 1 we will determine the optimal
Cas9 ortholog and guide RNA sequence for AAV-mediated site specific disruption of the Ldlr gene in mouse
liver. In Aim 2, we will use these vectors, along with a recombinant AAV genome harboring a “repair template”
to deliver the functional “wild type” exon for Ldlr. The extent of editing and correction will be assessed at the
genetic as well as phenotypic levels- include changes in plasma lipids and susceptibility to atherosclerosis.
Completion of the aims will produce a powerful AAV-based system for somatic gene knockdown and repair in
the liver, which can be broadly applied for both basic science and gene therapy applications.

## Key facts

- **NIH application ID:** 9838265
- **Project number:** 5R01HL132840-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** William Raymond Lagor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $645,390
- **Award type:** 5
- **Project period:** 2016-12-20 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838265

## Citation

> US National Institutes of Health, RePORTER application 9838265, Genetic Repair of Familial Hypercholesterolemia (5R01HL132840-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9838265. Licensed CC0.

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