dCasMINI-mediated therapy rescues photoreceptors degeneration in a mouse model of retinitis pigmentosa
Retinitis pigmentosa (RP) is characterized by degeneration of rod and cone photoreceptors that progresses to irreversible blindness. Now, there are no mutation-agnostic approaches to treat RP. Here, we utilized a single adeno-associated virus (AAV)-based CRISPR activation system to activate phosphodiesterase 6B (Pde6b) to mitigate the severe degeneration in <i>Pde6a</i><sup>nmf363</sup> mice. We demonstrate that transcriptional activation of <i>Pde6b</i> can rescue the loss of <i>Pde6a</i>, with preservation of retinal structure, restoration of electroretinography responses, and improvement of visual function as assessed by optokinetic response and looming-induced escape behaviors. These findings demonstrate the therapeutic potential of a dCasMINI-mediated activation strategy that provides a mutation-independent treatment for retinal degeneration. This study offers a promising therapeutic approach for RP and potentially other forms of genetic diseases.
Authors
- Sui Wang (ORCID: https://orcid.org/0000-0003-1563-9117)
- Lei S. Qi (ORCID: https://orcid.org/0000-0002-3965-3223)
- Zhiquan Liu (ORCID: https://orcid.org/0000-0001-5433-5656)
- M. Elizabeth Hartnett (ORCID: https://orcid.org/0000-0002-7270-5670)
- Xiaoshu Xu (ORCID: https://orcid.org/0000-0002-2989-4007)
- Yang Sun (ORCID: https://orcid.org/0000-0001-8735-4765)
- Ke Ning (ORCID: https://orcid.org/0000-0001-8994-3803)
- Tia J. Kowal (ORCID: https://orcid.org/0000-0003-3879-4718)
- Siyu Chen (ORCID: https://orcid.org/0000-0002-0692-9748)
- Chien‐Hui Lo (ORCID: https://orcid.org/0000-0001-9016-0953)
- Liang Li (ORCID: https://orcid.org/0000-0002-6562-7838)
- Biao Wang
- Rui Lu (ORCID: https://orcid.org/0000-0002-5238-1592)
- Tingting Li (ORCID: https://orcid.org/0009-0007-0461-0024)
- Qing Wang (ORCID: https://orcid.org/0009-0006-8194-5680)
Institutions
- Palo Alto University (US)
- Palo Alto Veterans Institute for Research (US)
- Stanford Health Care (US)
- Chan Zuckerberg Initiative (United States) (US)
- Shanghai East Hospital (CN)
- Stanford Medicine (US)
- Smith-Kettlewell Eye Research Institute (US)
- Stanford University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1126/sciadv.adn7540
- Citations
- 4
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.94