Nanocarrier-Mediated Gene Delivery for Treatment of Inherited Retinal Disorders

Minh Nguyen; T. Tran; L. Le

doi:10.5281/zenodo.22849441

Authors

Minh Nguyen Department of Health Sciences, Phnom Penh Institute of Applied Nanoscience Author https://orcid.org/7810-7954-1123-8676
T. Tran Department of Health Sciences, Hanoi Institute of Nanomedicine Author https://orcid.org/6212-3129-0070-5917
L. Le Department of Clinical Research, Hanoi Institute of Nanomedicine Author https://orcid.org/7975-8232-9942-2359

DOI:

https://doi.org/10.5281/zenodo.22849441

Keywords:

gene therapy, nanocarrier, inherited retinal disorders, adeno-associated virus, compacted DNA nanoparticles

Abstract

Adeno-associated virus (AAV) is now a clinically approved delivery vehicle for inherited retinal disorders, but its fixed packaging capacity, pre-existing population seroprevalence, and re-dosing limitations leave a meaningful gap for genes too large to package and for patients who cannot safely receive a second viral injection. This article synthesizes the literature on nanocarrier-mediated gene delivery to the retina as a complementary response to that gap, tracing the field from the AAV benchmark set by voretigene neparvovec and choroideremia gene therapy through the non-viral nanocarrier chemistries -- compacted DNA nanoparticles, glycol chitosan condensates, and PAMAM dendrimers -- that have been developed specifically for photoreceptor and retinal pigment epithelial delivery, the quantitative physical barriers the vitreous imposes on any intravitreally delivered particle, and the newer dual-AAV and AAV-delivered CRISPR-Cas9 architectures that address the same large-cargo and precision-editing problems from a different direction. Read together, the evidence supports compacted DNA nanoparticles as the most thoroughly characterized non-viral retinal platform to date, with faster onset than AAV, a favorable local safety profile, and biodistribution confined to the treated eye, while leaving transduction-efficiency parity with AAV, large-animal and human validation, and repeat-dosing safety data as an open preclinical agenda before any non-viral retinal nanocarrier can plausibly reach a first-in-human trial.

References

Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, et al. (2017) Efficacy and Safety of Voretigene Neparvovec (AAV2-hRPE65v2) in Patients with RPE65-Mediated Inherited Retinal Dystrophy: A Randomised, Controlled, Open-Label, Phase 3 Trial. The Lancet, 390(10097): 849-860. DOI: 10.1016/S0140-6736(17)31868-8

Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, et al. (2008) Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis. New England Journal of Medicine, 358(21): 2240-2248. DOI: 10.1056/NEJMoa0802315

Bainbridge JWB, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, et al. (2008) Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis. New England Journal of Medicine, 358(21): 2231-2239. DOI: 10.1056/NEJMoa0802268

Adijanto J, Naash MI (2015) Nanoparticle-Based Technologies for Retinal Gene Therapy. European Journal of Pharmaceutics and Biopharmaceutics, 95(Pt B): 353-367. DOI: 10.1016/j.ejpb.2014.12.028

Cideciyan AV, Hauswirth WW, Aleman TS, Kaushal S, Schwartz SB, Boye SL, Windsor EAM, Conlon TJ, Sumaroka A, Roman AJ, et al. (2009) Vision 1 Year after Gene Therapy for Leber's Congenital Amaurosis. New England Journal of Medicine, 361(7): 725-727. DOI: 10.1056/NEJMc0903652

Simonelli F, Maguire AM, Testa F, Pierce EA, Mingozzi F, Bennicelli JL, Rossi S, Marshall K, Banfi S, Surace EM, et al. (2010) Gene Therapy for Leber's Congenital Amaurosis Is Safe and Effective Through 1.5 Years After Vector Administration. Molecular Therapy, 18(3): 643-650. DOI: 10.1038/mt.2009.277

MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FPM, Black GCM, et al. (2014) Retinal Gene Therapy in Patients with Choroideremia: Initial Findings from a Phase 1/2 Clinical Trial. The Lancet, 383(9923): 1129-1137. DOI: 10.1016/S0140-6736(13)62117-0

Fischer MD, McClements ME, Martinez-Fernandez de la Camara C, Bellingrath JS, Dauletbekov D, Ramsden SC, Hickey DG, Barnard AR, MacLaren RE (2017) Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa. Molecular Therapy, 25(8): 1854-1865. DOI: 10.1016/j.ymthe.2017.05.005

Piotter E, McClements ME, MacLaren RE (2021) Therapy Approaches for Stargardt Disease. Biomolecules, 11(8): 1179. DOI: 10.3390/biom11081179

Ding XQ, Quiambao AB, Fitzgerald JB, Cooper MJ, Conley SM, Naash MI (2009) Ocular Delivery of Compacted DNA-Nanoparticles Does Not Elicit Toxicity in the Mouse Retina. PLoS ONE, 4(10): e7410. DOI: 10.1371/journal.pone.0007410

Han Z, Conley SM, Naash MI (2011) AAV and Compacted DNA Nanoparticles for the Treatment of Retinal Disorders: Challenges and Future Prospects. Investigative Ophthalmology & Visual Science, 52(6): 3051-3059. DOI: 10.1167/iovs.10-6916

Han Z, Koirala A, Makkia R, Cooper MJ, Naash MI (2012) Direct Gene Transfer with Compacted DNA Nanoparticles in Retinal Pigment Epithelial Cells: Expression, Repeat Delivery and Lack of Toxicity. Nanomedicine (London), 7(4): 521-539. DOI: 10.2217/nnm.11.158

Han Z, Conley SM, Makkia R, Guo J, Cooper MJ, Naash MI (2012) Comparative Analysis of DNA Nanoparticles and AAVs for Ocular Gene Delivery. PLoS ONE, 7(12): e52189. DOI: 10.1371/journal.pone.0052189

Mitra RN, Han Z, Merwin M, Al Taai M, Conley SM, Naash MI (2014) Synthesis and Characterization of Glycol Chitosan DNA Nanoparticles for Retinal Gene Delivery. ChemMedChem, 9(1): 189-196. DOI: 10.1002/cmdc.201300371

Mastorakos P, Kambhampati SP, Mishra MK, Wu T, Song E, Hanes J, Kannan RM (2015) Hydroxyl PAMAM Dendrimer-Based Gene Vectors for Transgene Delivery to Human Retinal Pigment Epithelial Cells. Nanoscale, 7(9): 3845-3856. DOI: 10.1039/c4nr04284k

Cai X, Conley SM, Nash Z, Fliesler SJ, Cooper MJ, Naash MI (2010) Gene Delivery to Mitotic and Postmitotic Photoreceptors via Compacted DNA Nanoparticles Results in Improved Phenotype in a Mouse Model of Retinitis Pigmentosa. The FASEB Journal, 24(4): 1178-1191. DOI: 10.1096/fj.09-139147

Han Z, Banworth MJ, Makkia R, Conley SM, Al-Ubaidi MR, Cooper MJ, Naash MI (2015) Genomic DNA Nanoparticles Rescue Rhodopsin-Associated Retinitis Pigmentosa Phenotype. The FASEB Journal, 29(6): 2535-2544. DOI: 10.1096/fj.15-270363

Xu Q, Boylan NJ, Suk JS, Wang YY, Nance EA, Yang JC, McDonnell PJ, Cone RA, Duh EJ, Hanes J (2013) Nanoparticle Diffusion in, and Microrheology of, the Bovine Vitreous Ex Vivo. Journal of Controlled Release, 167(1): 76-84. DOI: 10.1016/j.jconrel.2013.01.018

Li Q, Weng J, Wong SN, Lee WYT, Chow SF (2021) Nanoparticulate Drug Delivery to the Retina. Molecular Pharmaceutics, 18(2): 506-521. DOI: 10.1021/acs.molpharmaceut.0c00224

Battaglia L, Serpe L, Foglietta F, Muntoni E, Gallarate M, Del Pozo Rodriguez A, Solinis MA (2016) Application of Lipid Nanoparticles to Ocular Drug Delivery. Expert Opinion on Drug Delivery, 13(12): 1743-1757. DOI: 10.1080/17425247.2016.1201059

Trapani I, Colella P, Sommella A, Iodice C, Cesi G, de Simone S, Marrocco E, Rossi S, Giunti M, Palfi A, et al. (2014) Effective Delivery of Large Genes to the Retina by Dual AAV Vectors. EMBO Molecular Medicine, 6(2): 194-211. DOI: 10.1002/emmm.201302948

Trapani I, Toriello E, de Simone S, Colella P, Iodice C, Polishchuk EV, Sommella A, Colecchi L, Rossi S, Simonelli F, et al. (2015) Improved Dual AAV Vectors with Reduced Expression of Truncated Proteins Are Safe and Effective in the Retina of a Mouse Model of Stargardt Disease. Human Molecular Genetics, 24(23): 6811-6825. DOI: 10.1093/hmg/ddv386

Pierce EA, Aleman TS, Jayasundera KT, Ashimatey BS, Kim K, Rashid A, Jaskolka MC, Myers RL, Lam BL, Bailey ST, Comander JI, Lauer AK, Maguire AM, Pennesi ME (2024) Gene Editing for CEP290-Associated Retinal Degeneration. New England Journal of Medicine, 390(21): 1972-1984. DOI: 10.1056/NEJMoa2309915

Nanocarrier-Mediated Gene Delivery for Treatment of Inherited Retinal Disorders

Authors

DOI:

Keywords:

Abstract

References

Downloads

Published

Issue

Section

License