# Folding Assisted therapeutics for Achromatopsia

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $237,750

## Abstract

PROJECT SUMMARY
Cyclic nucleotide gated channels (CNG) transduce light information into membrane potential changes in cone
photoreceptors. Mutations in CNGA3 and CNGB3, genes encoding CNG channel subunits are the most
common cause of achromatopsia (ACHM), an autosomal recessive channelopathy producing incomplete or
complete loss of cone function. Patients have poor visual acuity, lack of color discrimination, photophobia and
day blindness. Over 100 missense mutations in CNGA3 have been identified in patients with ACHM2, the
majority being compound heterozygotes. A subset of CNGA3 mutations studied in heterologous systems
showed functional rescue when cells were grown at low temperatures. These mutations likely have folding
defects resulting in endoplasmic reticulum (ER)-retained subunits causing loss of channel function. We
hypothesized that ER-retained mutants might be rescued with small molecule correctors to restore channel
function as a new therapeutic approach for ACHM2. Small molecule correctors of the most common cystic
fibrosis mutation, CFTR F508del have been identified and led to an FDA-approved treatment. Correctors
identified from high-throughput screening on CFTR F508del show broad utility to improve function of other
mutant proteins associated with inherited channelopathies. As a therapeutic strategy, we hypothesize that
misfolded CNGA3 subunits might also respond to small molecule correctors and restore channel function. We
developed a high-throughput calcium influx assay based on the calcium permeability of cone CNG channels; a
permeant, cGMP analog was used to activate the calcium influx. Using this functional assay together with
cellular localization utilizing YFP-tagged mutant channels, we will in Aim 1, characterize mutant CNGA3
channels to identify mutations which exhibit improved function in response to reduced temperature as an
indicator of receptivity to rescue. Our cellular localization assay identifies ER-retained mutants and will be used
as a secondary screen to assist in selecting misfolded mutants. In Aim 2, mutant CNGA3 channels will be
screened against a collection of known correctors in the calcium influx assay to identify compounds which
improve channel activity. Active compounds will be characterized in the localization assay to confirm their
mechanism as fold-assist by shifting the distribution of mutant channels from the ER to increased membrane
expression. Completion of these aims will result in a deeper understanding of the molecular basis of ACHM2
and has potential for identifying small molecules as the first step toward a pharmacological treatment for
ACHM2.

## Key facts

- **NIH application ID:** 9964823
- **Project number:** 5R21EY030257-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** MARLENE A JACOBSON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,750
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964823

## Citation

> US National Institutes of Health, RePORTER application 9964823, Folding Assisted therapeutics for Achromatopsia (5R21EY030257-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9964823. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*