Intravitreal gene therapy

Intravitreal gene therapy represents an approach to treating retinal diseases by delivering therapeutic genes directly into the vitreous humor of the eye.[1] This method uses a viral vector, often an adeno-associated virus (AAV), to carry genetic material into retinal cells. Once inside, the therapeutic genes are expressed to address genetic deficiencies or modify biological pathways, offering a long-term or potentially permanent treatment ("biofactory approach") for conditions like wet age-related macular degeneration (AMD), diabetic macular edema, and inherited retinal dystrophies.[2] Unlike traditional therapies requiring frequent injections, intravitreal gene therapy aims to reduce the treatment burden while improving efficacy potentially providing lifelong benefit.

## Contents

* 1 Advantages and challenges
* 2 Investigational agents
* 3 References

## Advantages and challenges

One of the key advantages of intravitreal administration is its minimally invasive nature compared to subretinal delivery.[3] Intravitreal injections are already commonly used for administering drugs like anti-VEGF agents, making the procedure familiar to clinicians and safer for patients. The eye's immune-privileged status reduces the likelihood of immune responses to the viral vector, increasing the therapy's safety profile. Emerging clinical trials are exploring this modality's potential, with promising results indicating sustained benefits over months or years after a single treatment.[citation needed]

Despite its potential, challenges remain. One major hurdle is ensuring efficient transduction of retinal cells via the intravitreal route, as the viral vectors must traverse physical and biological barriers. Additionally, safety concerns, such as inflammation or unintended effects on neighboring cells, must be carefully monitored. Ongoing innovations in vector design and delivery systems aim to address these issues, paving the way for broader applications of intravitreal gene therapy in ophthalmology. This field continues to evolve, offering hope for more effective and less invasive treatments for debilitating eye diseases.[citation needed]

## Investigational agents

Investigational agents for intravitreal and subretinal gene therapies are advancing rapidly, targeting various retinal disorders. In neovascular age-related macular degeneration (nAMD), key intravitreal agents include Adverum Biotechnologies' ixoberogene soroparvovec (Ixo-vec) and 4D Molecular Therapeutics' 4D-150.[4] Both use innovative mechanisms to produce anti-VEGF proteins directly within the eye, significantly reducing the need for frequent anti-VEGF injections. Janssen's JNJ-1887 targets dry AMD with a complement pathway approach, while other agents like RGX-314 from REGENXBIO focus on sustained anti-VEGF effects delivered via subretinal routes.[5][6] These therapies demonstrate promising improvements in retinal structure and vision while minimizing treatment burdens.[citation needed]

For inherited retinal diseases, several subretinal therapies are in advanced stages.[7] MeiraGTx's botaretigene sparoparvovec targets X-linked retinitis pigmentosa through RPGR gene restoration and Beacon Therapeutics' laruparetigene zosaparvovec aims at similar conditions, showing retinal sensitivity improvements in trials.[8] Another notable effort is Atsena Therapeutics' ATSN-201 for X-linked retinoschisis.[9] These therapies focus on gene replacement to preserve or restore vision. However, challenges such as delivery complexities and immunogenicity remain.[citation needed]

Future directions include improving delivery techniques like suprachoroidal catheter systems, which avoid invasive procedures, and addressing scalability and cost concerns.[10] The goal is to transform these therapies into accessible options, providing lasting benefits and potentially revolutionizing care for both common and rare retinal disorders .[citation needed]

## References

1. ↑ "Retina Society 2024: Advances in AMD therapy highlight different mechanisms of action with a common goal" (in en). 2024-09-15. https://www.ophthalmologytimes.com/view/retina-society-2024-advances-in-amd-therapy-highlight-different-mechanisms-with-a-common-goal.
2. ↑ "Retinal Physician Special Edition 2020: The Eye As A Biofactory" (in en-US). https://digital.retinalphysician.com/articles/the-eye-as-a-biofactory.
3. ↑ Ross, Maya; Ofri, Ron (2021). "The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery" (in en). Neural Regeneration Research 16 (9): 1751–1759. doi:10.4103/1673-5374.306063. ISSN 1673-5374. PMID 33510064.
4. ↑ Khanani, Arshad M.; Boyer, David S.; Wykoff, Charles C.; Regillo, Carl D.; Busbee, Brandon G.; Pieramici, Dante; Danzig, Carl J.; Joondeph, Brian C. et al. (2024). "Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study". Lancet eClinicalMedicine 67. doi:10.1016/j.eclinm.2023.102394. PMID 38152412.
5. ↑ Campochiaro, Peter A; Avery, Robert; Brown, David M; Heier, Jeffrey S; Ho, Allen C; Huddleston, Stephen M; Jaffe, Glenn J; Khanani, Arshad M et al. (2024). "Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study" (in en). The Lancet 403 (10436): 1563–1573. doi:10.1016/S0140-6736(24)00310-6. PMID 38554726. https://linkinghub.elsevier.com/retrieve/pii/S0140673624003106.
6. ↑ "RGX-314 Gene Therapy Trial Shows Promise in Treating Wet Macular Degeneration" (in en). https://www.houstonmethodist.org/leading-medicine-blog/articles/2024/aug/rgx-314-gene-therapy-trial-shows-promise-in-treating-wet-macular-degeneration/.
7. ↑ Georgiou, Michalis; Fujinami, Kaoru; Michaelides, Michel (2021). "Inherited retinal diseases: Therapeutics, clinical trials and end points—A review" (in en). Clinical & Experimental Ophthalmology 49 (3): 270–288. doi:10.1111/ceo.13917. ISSN 1442-6404. PMID 33686777.
8. ↑ Michaelides, Michel; Besirli, Cagri G.; Yang, Yesa; De Guimaraes, Thales A.C.; Wong, Sui Chien; Huckfeldt, Rachel M.; Comander, Jason I.; Sahel, José-Alain et al. (2024). "Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa" (in en). American Journal of Ophthalmology 267: 122–134. doi:10.1016/j.ajo.2024.05.034. PMID 38871269.
9. ↑ "Christine N. Kay, MD: Interim Data on ATSN-201 Shows Promise for XLRS" (in en). 2024-10-23. https://www.hcplive.com/view/christine-n-kay-md-interim-data-on-atsn-201-shows-promise-for-xlrs.
10. ↑ Felder, Anthony E.; Leiderman, Yannek I.; Tomback, Matthew; Chicano, Aaron; Burek, Manuela; Arendovich, Xenon; Wilkens, Kimberlee; Frisbie, Charles et al. (2020-11-16). "Design of a navigational catheter system for the targeted delivery of therapeutics within the suprachoroidal space" (in en). Journal of Medical Engineering & Technology 44 (8): 508–516. doi:10.1080/03091902.2020.1831632. ISSN 0309-1902. PMID 33118388.

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