Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases
Grant Award Details
Grant Type:
Grant Number:
DISC2-10973
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$1,153,937
Status:
Closed
Progress Reports
Reporting Period:
Year 2
Reporting Period:
NCE
Grant Application Details
Application Title:
Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases
Public Abstract:
Research Objective
We will discover small molecule compounds that correct disease in eyecups (retinal organoids) differentiated from patient iPSCs with photoreceptor diseases.
Impact
Our small molecule agents will provide new treatments for achromatopsia and cone-rod dystrophy. These are rare hereditary blinding diseases with no cures
Major Proposed Activities
We will discover small molecule compounds that correct disease in eyecups (retinal organoids) differentiated from patient iPSCs with photoreceptor diseases.
Impact
Our small molecule agents will provide new treatments for achromatopsia and cone-rod dystrophy. These are rare hereditary blinding diseases with no cures
Major Proposed Activities
- Transcriptomic and proteomic profiling of control and diseased iPSC-differentiated eyecups after ATF6 agonist treatment.
- Define the potential for ATF6 agonists to improve photoreceptor protein folding and function in patient iPSC-differentiated eyecups.
- Demonstrate that ATF6 agonists increase survival of patient iPSC-differentiated eyecups under ER stress and protein misfolding conditions.
- Transcriptomic and proteomic profiling of control and diseased iPSC-differentiated eyecups after XBP1s agonist treatment.
- Define the potential for XBP1s agonists to improve photoreceptor protein folding and function in patient iPSC-differentiated eyecups
- Demonstrate that XBP1s agonists increase survival of patient iPSC-differentiated eyecups under ER stress and protein misfolding conditions.
Statement of Benefit to California:
The proposed research will benefit the citizens of California by identifying new treatments for rare orphan vision loss diseases that currently have no cure. The proposed research will benefit the State of California by improving the visual acuity and color perception of California citizens with these diseases so that they can meaningfully engage in daily activities and pursue career and educational objectives with better quality-of-life outcomes.
Publications
- Proc Natl Acad Sci U S A (2021): ATF6 is essential for human cone photoreceptor development. (PubMed: 34561305)
- JCI Insight (2020): Multiexon deletion alleles of ATF6 linked to achromatopsia. (PubMed: 32271167)
