The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease
Abstract
:1. Introduction
2. Genomics of Inherited Retinal Disease
3. Neuroprotection
3.1. N-Acetylcysteine and Antioxidant Therapies for Neuroprotection
3.2. Pharmacological and Neuroprotective Strategies for the Treatment of Stargardt Disease
3.3. Neurotrophic Factors and Stem-Cell Based Therapies for Neuroprotection
4. Gene Replacement Therapies: Early Successes and Future Challenges
4.1. Improving Cell-Type Specificity and Delivery Efficiency of AAV Vectors
4.2. Non-Viral Gene Delivery Strategies
5. RNA-Modifying Therapies for Inherited Retinal Degenerations
6. Gene Editing Technologies
6.1. CRISPR-Cas9 Genome Editing
6.2. Advanced Gene-Editing Technologies
6.3. Gene Editing and the Treatment of Retinal Disease
7. Restoring Light Sensitivity to the Retina with Optogenetics
8. Retinal Cell Replacement Therapies
8.1. Stem Cell- Derived Photoreceptor Cells
8.2. Retinal Pigmented Epithelium (RPE) Cells
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Condition | Phase | Vector/Drug | Gene | Prevalence | Allele Mechanism | Sponsor | Status |
---|---|---|---|---|---|---|---|
Adeno-Associated Virus Vector Gene Therapies | |||||||
Achromatopsia | 1/2 | AAV2tYF | CNGB3 | 50% [21] | LOF | Applied Genetic Technologies Corp | Recruiting |
1/2 | AAV2/8 | CNGB3 | “ | “ | MeiraGTx | Completed | |
1/2 | AAV2tYF | CNGA3 | 25% [21] | LOF | Applied Genetic Technologies Corp | Recruiting | |
1/2 | AAV2/8 | CNGA3 | “ | “ | MeiraGTx | Recruiting | |
1/2 | AAV8 | CNGA3 | “ | “ | STZ Eyetrial | Recruiting | |
X-Linked Retinoschisis | 1/2 | AAV2tYF | RS1 | 100% [22] | LOF | Applied Genetic Technologies Corp | Recruiting |
1/2 | AAV8 | RS1 | “ | “ | National Institutes of Health | Recruiting | |
X-Linked RP | 1/2 | AAV2/5 | RPGR | 75% [23] | LOF | MeiraGTx | Recruiting |
1/2 | AAV(4D-R100) | RPGR | “ | “ | 4D Molecular Therapeutics | Recruiting | |
1/2 > 2 | AAV2tYF | RPGR | “ | “ | Applied Genetic Technologies Corp | Recruiting | |
2 > 3 | AAV2/8 | RPGR | “ | “ | Biogen/NightstaRx | Recruiting | |
Autosomal Recessive RP (arRP) | 1/2 | AAV2/5 | PDE6B | 4% [24] | LOF | Horama S.A. | Recruiting |
1/2 | AAV8 | RLBP1 | 1% [25] | “ | Novartis | Recruiting | |
1/2 | AAV2 | MERTK | 4% [26] | “ | King Khaled Eye Specialist Hospital | Completed | |
Choroideremia | 1 | AAV2 | REP1 | 100% [27] | LOF | 4D Molecular Therapeutics | Recruiting |
1/2 | AAV2 | REP1 | “ | “ | Spark Therapeutics | Active, Not Recruiting | |
2 | AAV2 | REP1 | “ | “ | STZ Eyetrial | Completed | |
2 | AAV2 | REP1 | “ | “ | University of Oxford | Completed | |
2 | AAV2 | REP1 | “ | “ | Bascom Palmer/University of Miami | Completed | |
1/2 | AAV2 | REP1 | “ | “ | University of Alberta | Completed | |
3 | AAV2 | REP1 | “ | “ | Biogen/NightstaRx | Completed | |
LCA2/arRP | Approved | AAV2 | RPE65 | 6% LCA [28], 2% arRP [29] | LOF | Spark Therapeutics | Treating |
LCA1 | 1/2 | AAV5 | GUCY2D | 10–20% [30] | LOF | Atsena Therapeutics | Recruiting |
Lentivirus Vector Gene Therapies | |||||||
Stargardt Disease | 1/2 | EIAV | ABCA4 | 100% [31] | LOF | Sanofi | Terminated |
Usher Syndrome 1B | 1/2 | EIAV | MYO7A | 21% [32] | LOF | Sanofi | Terminated |
Antisense Oligonucleotides | |||||||
Usher Syndrome 2/ arRP | 1/2 | QR-421a | USH2A (exon 13) | ~20% US2, 4% arRP [33,34,35] †† | frame-shift/LOF | ProQR Therapeutics | Recruiting |
RP | 1/2 | QR-1123 | RHO(P23H) | 10% [36] †† | missense/dominant negative | ProQR Therapeutics | Recruiting |
LCA10 | 1/2 | Sepofarsen (QR-110) | CEP290(p.Cys998X) | 10–15% of LCA [37] †† | splice-donor site/insertion | ProQR Therapeutics | Recruiting |
Gene editing/ CRISPR Cas9 | |||||||
LCA10 | 1/2 | EDIT-101 | CEP290(p.Cys998X) | 10–15% of LCA [37] †† | splice-donor site/insertion | Editas Medicine | Recruiting |
Optogenetics | |||||||
RP | 1/2 | AAV2-7m8-ChrimsonR-tdTomato | *** | GenSight Biologics | Recruiting | ||
1/2 | AAV2-ChR2 | *** | Allergan | Active, Not Recruiting | |||
2 | AAV2-MCO-010 | *** | Nanoscope Therapeutics | Recruiting | |||
Antioxidants and neuroprotection | |||||||
RP | 1 | N-acetylcysteine | *** | Johns Hopkins University | Active, Not Recruiting | ||
Usher Syndromes | 1/2 | NPI-001 tablets | *** | Nacuity Pharmaceuticals Foundation Finding Blindness | Recruiting | ||
Stargardt Disease | 2 | ALK-001 | ABCA4 | 100% [31] | LOF | Alkeus Pharmaceuticals | Recruiting |
2 | STG-001 | “ | “ | “ | Stargazer Pharmaceutical | Completed | |
2 | avacincaptad pegol (Zimura) | “ | “ | “ | IVERIC Bio | Recruiting | |
3 | Emixustat | “ | “ | “ | Kubota Vision | Active, Not Recruiting | |
Stem cells and cell-based therapies | |||||||
RP | 1 | intravitreal CD34+ Stem Cells | *** | University of California, Davis Cures within Reach | Recruiting | ||
1/2 | subretinal hRPCs | *** | ReNeuron Limited | Recruiting | |||
2 | intravitreal hRPCs | *** | jCyte | Active, Not Recruiting | |||
Stargardt Disease | 1/2 | Subretinal injection of human embryonic stem cell-derived RPE cells | Astellas Institute for Regenerative Medicine | Completed |
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Martinez Velazquez, L.A.; Ballios, B.G. The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease. Int. J. Mol. Sci. 2021, 22, 11542. https://doi.org/10.3390/ijms222111542
Martinez Velazquez LA, Ballios BG. The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease. International Journal of Molecular Sciences. 2021; 22(21):11542. https://doi.org/10.3390/ijms222111542
Chicago/Turabian StyleMartinez Velazquez, Luis A., and Brian G. Ballios. 2021. "The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease" International Journal of Molecular Sciences 22, no. 21: 11542. https://doi.org/10.3390/ijms222111542