Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody

Gene Therapy volume 31, pages 587–593 (2024)Cite this article

Subjects

Abstract

Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block choroidal neovascularization (CNV) induced by subretinal injection of Matrigel in a mouse model. Intravitreal AAV-anti-Scg3Fab significantly reduced CNV and suppressed CNV-associated leukocyte infiltration and macrophage activation. The efficacy and anti-inflammatory effects were equivalent to those achieved by positive control AAV-aflibercept against VEGF. Efficacies of AAV-anti-Scg3Fab and AAV-aflibercept were sustained over 4 months post AAV delivery. The findings support development of AAV-anti-Scg3 as an alternative to AAV-anti-VEGF with equivalent efficacy and potentially safer mechanism of action.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Expression of anti-Scg3 Fab and aflibercept by AAVs in HEK293 cells and retinas.
Fig. 2: Inhibition of CNV lesion by AAV-aflibercept and AAV-antiScg3Fab.
Fig. 3: Short-term therapeutic efficacy of AAV-anti-Scg3Fab and AAV-aflibercept to alleviate Matrigel-induced CNV.
Fig. 4: Anti-inflammation effect of AAV-aflibercept and AAV-antiScg3hFab.
Fig. 5: Long-term efficacy of AAV-anti-Scg3Fab and AAV-aflibercept to ameliorate MCNV.

Similar content being viewed by others

Data availability

Data and images generated during the current study are available from the corresponding author upon reasonable request.

References

  1. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106–116.

    Article  PubMed  Google Scholar 

  2. Jager RD, Aiello LP, Patel SC, Cunningham ET. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676–98.

    Article  PubMed  Google Scholar 

  3. Cox JT, Eliott D, Sobrin L. Inflammatory Complications of Intravitreal Anti-VEGF Injections. J Clin Med. 2021;10:981.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Cheng S-Y, Luo Y, Malachi A, Ko J, Su Q, Xie J, et al. Low-Dose Recombinant Adeno-Associated Virus-Mediated Inhibition of Vascular Endothelial Growth Factor Can Treat Neovascular Pathologies Without Inducing Retinal Vasculitis. Hum Gene Ther. 2021;32:649–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Dai C, Waduge P, Ji L, Huang C, He Y, Tian H, et al. Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy. Cell Mol Life Sci. 2022;79:63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Goldhardt R, Batawi HIM, Rosenblatt M, Lollett IV, Park JJ, Galor A. Effect of Anti-Vascular Endothelial Growth Factor Therapy on Corneal Nerves. Cornea 2019;38:559–64.

    Article  PubMed  Google Scholar 

  7. Zhu Z-Y, Meng Y-A, Yan B, Luo J. Effect of anti-VEGF treatment on nonperfusion areas in ischemic retinopathy. Int J Ophthalmol. 2021;14:1647–52.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Elnahry AG, Abdel-Kader AA, Habib AE, Elnahry G, Raafat KA, Elrakhawy K. Review on Recent Trials Evaluating the Effect of Intravitreal Injections of Anti-VEGF Agents on the Macular Perfusion of Diabetic Patients with Diabetic Macular Edema. Rev Recent Clin Trials. 2020;15:188–98.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Abri Aghdam K, Reznicek L, Soltan Sanjari M, Klingenstein A, Kernt M, Seidensticker F. Anti-VEGF treatment and peripheral retinal nonperfusion in patients with central retinal vein occlusion. Clin Ophthalmol. 2017;11:331–6.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Resch MD, Balogh A, Deák GG, Nagy ZZ, Papp A. Vascular density in age-related macular degeneration after one year of antiVEGF treatment with treat-and-extend and fixed regimens. PLoS One. 2020;15:e0229388.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Ray SK, Manz SN. Brain health assessment in macular degeneration patients undergoing intravitreal anti-vascular endothelial growth factor injections (the bham study): An Interim Analysis. Retina. 2021;41:1748–53.

    Article  PubMed  CAS  Google Scholar 

  12. Sultana J, Scondotto G, Cutroneo PM, Morgante F, Trifirò G. Intravitreal Anti-VEGF Drugs and Signals of Dementia and Parkinson-Like Events: Analysis of the VigiBase Database of Spontaneous Reports. Front Pharm. 2020;11:315.

    Article  Google Scholar 

  13. Dedania VS, Bakri SJ. Current perspectives on ranibizumab. Clin Ophthalmol. 2015;9:533–42.

    PubMed  PubMed Central  Google Scholar 

  14. Khanani AM, Thomas MJ, Aziz AA, Weng CY, Danzig CJ, Yiu G, et al. Review of gene therapies for age-related macular degeneration. Eye. 2022;36:303–11.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Castro BFM, Steel JC, Layton CJ. AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies. BioDrugs. 2024;38:73–93.

    Article  PubMed  Google Scholar 

  16. Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019;176:1248–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Dunn EN, Hariprasad SM, Sheth VS. An Overview of the Fovista and Rinucumab Trials and the Fate of Anti-PDGF Medications. Ophthalmic Surg Lasers Imaging Retin. 2017;48:100–4.

    Article  Google Scholar 

  18. Reid CA, Nettesheim ER, Connor TB, Lipinski DM. Development of an inducible anti-VEGF rAAV gene therapy strategy for the treatment of wet AMD. Sci Rep. 2018;8:11763.

    Article  PubMed  PubMed Central  Google Scholar 

  19. LeBlanc ME, Wang W, Chen X, Caberoy NB, Guo F, Shen C, et al. Secretogranin III as a disease-associated ligand for antiangiogenic therapy of diabetic retinopathy. J Exp Med. 2017;214:1029–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Rong X, Tian H, Yang L, Li W. Function-first ligandomics for ocular vascular research and drug target discovery. Exp Eye Res. 2019;182:57–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Ji L, Waduge P, Wu Y, Huang C, Kaur A, Oliveira P, et al. Secretogranin III Selectively Promotes Vascular Leakage in the Deep Vascular Plexus of Diabetic Retinopathy. Int J Mol Sci. 2023;24:10531.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ji L, Waduge P, Hao L, Kaur A, Wan W, Wu Y, et al. Selectively targeting disease-restricted secretogranin III to alleviate choroidal neovascularization. FASEB J. 2022;36:e22106.

    Article  PubMed  CAS  Google Scholar 

  23. Huang C, Ji L, Kaur A, Tian H, Waduge P, Webster KA, et al. Anti-Scg3 Gene Therapy to Treat Choroidal Neovascularization in Mice. Biomedicines. 2023;11:1910.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. FDA. Drug information for Eylea. 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf.

  25. Droho S, Rajesh A, Cuda CM, Perlman H, Lavine JA. CD11c+ macrophages are proangiogenic and necessary for experimental choroidal neovascularization. JCI Insight. 2023;8:e168142.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Grishanin R, Vuillemenot B, Sharma P, Keravala A, Greengard J, Gelfman C, et al. Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration. Mol Ther. 2019;27:118–29.

    Article  PubMed  CAS  Google Scholar 

  27. Gelfman CM, Grishanin R, Bender KO, Nguyen A, Greengard J, Sharma P, et al. Comprehensive Preclinical Assessment of ADVM-022, an Intravitreal Anti-VEGF Gene Therapy for the Treatment of Neovascular AMD and Diabetic Macular Edema. J Ocul Pharm Ther. 2021;37:181–90.

    Article  CAS  Google Scholar 

  28. Lai C-M, Shen W-Y, Brankov M, Lai YKY, Barnett NL, Lee SY, et al. Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. Mol Ther. 2005;12:659–68.

    Article  PubMed  CAS  Google Scholar 

  29. Lukason M, DuFresne E, Rubin H, Pechan P, Li Q, Kim I, et al. Inhibition of choroidal neovascularization in a nonhuman primate model by intravitreal administration of an AAV2 vector expressing a novel anti-VEGF molecule. Mol Ther. 2011;19:260–5.

    Article  PubMed  CAS  Google Scholar 

  30. Hughes CP, O’Flynn NMJ, Gatherer M, McClements M, Scott JA, MacLaren R, et al. AAV2/8 Anti-angiogenic Gene Therapy Using Single-Chain Antibodies Inhibits Murine Choroidal Neovascularization. Mol Ther Methods Clin Dev. 2019;13:86–98.

    Article  PubMed  CAS  Google Scholar 

  31. Pennesi ME, Neuringer M, Courtney RJ. Animal models of age related macular degeneration. Mol Asp Med. 2012;33:487–509.

    Article  CAS  Google Scholar 

  32. Zandi S, Li Y, Jahnke L, Schweri-Olac A, Ishikawa K, Wada I, et al. Animal model of subretinal fibrosis without active choroidal neovascularization. Exp Eye Res. 2023;229:109428.

    Article  PubMed  CAS  Google Scholar 

  33. Zhao L, Wang Z, Liu Y, Song Y, Li Y, Laties AM, et al. Translocation of the retinal pigment epithelium and formation of sub-retinal pigment epithelium deposit induced by subretinal deposit. Mol Vis. 2007;13:873–80.

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Lai YKY, Shen WY, Brankov M, Lai CM, Constable IJ, Rakoczy PE. Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated virus-mediated secretion gene therapy. Gene Ther. 2002;9:804–13.

    Article  PubMed  CAS  Google Scholar 

  35. Rakoczy EP, Magno AL, Lai C-M, Magno A, Degli-Esposti MA, French MA, et al. Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. Am J Ophthalmol. 2019;204:113–23.

    Article  PubMed  Google Scholar 

  36. Constable IJ, Pierce CM, Lai CM, Magno AL, Degli-Esposti MA, French MA, et al. Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration. EBioMedicine. 2016;14:168–75.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Heier JS, Kherani S, Desai S, Dugel P, Kaushal S, Cheng SH, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet. 2017;390:50–61.

    Article  PubMed  CAS  Google Scholar 

  38. Khanani AM, Boyer DS, Wykoff CC, Regillo CD, Busbee BG, Pieramici D, et al. 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. EClinicalMedicine. 2024;67:102394.

    Article  PubMed  Google Scholar 

  39. Koponen S, Kokki E, Kinnunen K, Ylä-Herttuala S. Viral-Vector-Delivered Anti-Angiogenic Therapies to the Eye. Pharmaceutics. 2021;13:219.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H, et al. Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci USA. 2013;110:12018–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Calvo PM, Pastor AM, de la Cruz RR. Vascular endothelial growth factor: an essential neurotrophic factor for motoneurons? Neural Regen Res. 2018;13:1181–2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Sondell M, Sundler F, Kanje M. Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci. 2000;12:4243–54.

    Article  PubMed  CAS  Google Scholar 

  43. Arima M, Akiyama M, Fujiwara K, Mori Y, Inoue H, Seki E, et al. Neurodevelopmental outcomes following intravitreal bevacizumab injection in Japanese preterm infants with type 1 retinopathy of prematurity. PLoS One. 2020;15:e0230678.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Morin J, Luu TM, Superstein R, Ospina LH, Lefebvre F, Simard MN, et al. Neurodevelopmental Outcomes Following Bevacizumab Injections for Retinopathy of Prematurity. Pediatrics. 2016;137:e20153218.

    Article  PubMed  Google Scholar 

  45. Kiss S, Oresic Bender K, Grishanin RN, Hanna KM, Nieves JD, Sharma P, et al. Long-Term Safety Evaluation of Continuous Intraocular Delivery of Aflibercept by the Intravitreal Gene Therapy Candidate ADVM-022 in Nonhuman Primates. Transl Vis Sci Technol. 2021;10:34.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Tang F, LeBlanc ME, Wang W, Liang D, Chen P, Chou TH, et al. Anti-secretogranin III therapy of oxygen-induced retinopathy with optimal safety. Angiogenesis. 2019;22:369–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

Authors thank Drs. Yingbin Fu, Xiao Lin, Bojun Zhang, Prabuddha Waduge for scientific discussion and technical support.

Funding

This work was supported by NIH R01EY036417 (WL), R01EY027749 (WL), R24EY028764 (WL and KAW), R43EY031238 (HT, KAW and WL), R43EY032827 (HT and WL), R21EY035421 (WL), NIH P30EY002520, Knights Templar Eye Foundation Endowment in Ophthalmology (WL) and unrestricted institutional grants from Research to Prevent Blindness (RPB) to the Department of Ophthalmology, Baylor College of Medicine.

Author information

Authors and Affiliations

  1. Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, 77030, USA

    Chengchi Huang, Avinash Kaur, Liyang Ji, Keith A. Webster & Wei Li

  2. Everglades Biopharma, LLC, Houston, TX, 77098, USA

    Hong Tian & Keith A. Webster

  3. Department of Pharmacology, Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA

    Keith A. Webster

Authors
  1. Chengchi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Avinash Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liyang Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keith A. Webster
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CH, AK, LJ designed and implemented experiments, generated figures and analyzed data. HT constructed AAVs. KAW, HT, WL conceived and designed the projects, acquired funding and supervised the research. CH, WL wrote manuscripts. KAW, HT, WL revised manuscript. All authors have reviewed and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Wei Li.

Ethics declarations

Competing interests

HT and WL are shareholders of Everglades Biopharma, LLC and LigandomicsRx, LLC. WL is an inventor of issued and pending patents. The remaining authors declare no competing financial interests.

Ethical approval

All animal experiments were conducted in accordance with NIH guidelines and approved by the Institutional Animal Care and Use Committee at Baylor College of Medicine.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, C., Kaur, A., Ji, L. et al. Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody. Gene Ther 31, 587–593 (2024). https://doi.org/10.1038/s41434-024-00491-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-024-00491-9

Search

Advanced search

Quick links