# Antisense therapy for the treatment of visual loss in Usher syndrome

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2020 · $345,880

## Abstract

Project Summary
Individual rare diseases affect 6 – 8 % of the world population, which is limited compared to more common
diseases. Thus, developing therapeutics for these conditions generates little interest from the pharmaceutical
industry, resulting in a tremendous unmet medical need. However, development of therapies for rare diseases
– especially in the context of underlying genetic and molecular mechanisms -- represents an area of great
interest for the NIH. Usher syndrome is a rare disease characterized by concurrent hearing and vision loss.
The loss of both hearing and vision creates a major communication burden and affects all aspects of life
including health, education, social activities and employment. The long-term goals of this project are to develop
an effective treatment for vision loss in Usher using antisense therapy; and establish the clinical parameters
and measurable endpoints that could be used to determine the time to treatment and measure the potential
therapeutic effect of testing antisense oligonucleotides (ASO) in future clinical trials. Usher syndrome is
associated with mutations in sixteen genes creating four distinct clinical types. Usher-related genes and
proteins express multiple tissue-specific variants that change over time, which creates a barrier to therapeutic
strategies using gene-replacement therapy. To overcome this, we targeted the human 216A mutation in the
USH1C gene that causes Type 1C Usher in the Acadian population, with an ASO that modulates mutant RNA
splicing. Using a well validated Usher 1C mouse model that contains this human 216A mutation, we
demonstrated that ASO treatment improves splicing of the Ush1c-RNA transcript and shows appreciable and
significant rescue of vision and hearing. Therefore, the first aim of this study is to identify and characterize an
USH1C-ASO drug therapy molecule that most effectively targets the 216A mutation and treats vision loss. We
will test USH1C-targeted ASOs with different sequences and chemistries for efficacy and tolerability in Ush1c
mice and patients’ cells. The second aim is to determine the most robust clinical endpoints and identify
potential trial participants to guide a clinical trial. We have identified a cohort of 52 USH1C patients in the three
participating clinical centers. The patients will be invited to enroll in a prospective natural history study where
we will measure standard of care and novel retinal and visual parameters at 6-month intervals over a 2-year
period. These tests will allow us to define the clinical parameters to determine the outcome of our future trial.
Successful completion of the proposed studies, will identify a lead ASO-drug candidate, demonstrate its
preclinical efficacy, determine measurable clinical outcomes to guide a first-in-man ASO-based treatment for
vision loss in USH1C and identify a cohort of potential trial participants.

## Key facts

- **NIH application ID:** 10004041
- **Project number:** 5R01EY030499-02
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Jennifer Jean Lentz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,880
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004041

## Citation

> US National Institutes of Health, RePORTER application 10004041, Antisense therapy for the treatment of visual loss in Usher syndrome (5R01EY030499-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10004041. Licensed CC0.

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