Current developments of gene therapy in human diseases

Abstract

Gene therapy has witnessed substantial advancements in recent years, becoming a constructive tactic for treating various human diseases. This review presents a comprehensive overview of these developments, with a focus on their diverse applications in different disease contexts. It explores the evolution of gene delivery systems, encompassing viral (like adeno-associated virus; AAV) and nonviral approaches, and evaluates their inherent strengths and limitations. Moreover, the review delves into the progress made in targeting specific tissues and cell types, spanning the eye, liver, muscles, and central nervous system, among others, using these gene technologies. This targeted approach is crucial in addressing a broad spectrum of genetic disorders, such as inherited lysosomal storage diseases, neurodegenerative disorders, and cardiovascular diseases. Recent clinical trials and successful outcomes in gene therapy, particularly those involving AAV and the clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated proteins, are highlighted, illuminating the transformative potentials of this approach in disease treatment. The review summarizes the current status of gene therapy, its prospects, and its capacity to significantly ameliorate patient outcomes and quality of life. By offering comprehensive analysis, this review provides invaluable insights for researchers, clinicians, and stakeholders, enriching the ongoing discourse on the trajectory of disease treatment.

Keywords

AAV / clinical trials / CRISPR–Cas / gene therapy / human diseases

References

[1] Addison C. Spliced: boundary-work and the establishment of human gene therapy. BioSocieties. 2017; 12: 257-281.

[2] Sun W, Shi Q, Zhang H, et al. Advances in the techniques and methodologies of cancer gene therapy. Discov Med. 2019; 27(146): 45-55.

[3] Wang D, Gao G. State-of-the-art human gene therapy: part Ii. gene therapy strategies and applications. Discov Med. 2014; 18(98): 151.

[4] Maguire AM, Russell S, Chung DC, et al. Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years. Ophthalmology. 2021; 128(10): 1460-1468.

[5] Maguire AM, Russell S, Wellman JA, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in RPE65 mutation–associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019; 126(9): 1273-1285.

[6] Ciulla TA, Hussain RM, Berrocal AM, Nagiel A. Voretigene neparvovec-rzyl for treatment of RPE65-mediated inherited retinal diseases: a model for ocular gene therapy development. Expert Opin Biol Ther. 2020; 20(6): 565-578.

[7] Müller-Reible C. Principles, possibilities and limits of gene therapy. Z Kardiol. 1994; 83: 5-8.

[8] Sandhu JS, Keating A, Hozumi N. Human gene therapy. Crit Rev Biotechnol. 1997; 17(4): 307-326.

[9] Lundstrom K. New Era in Gene Therapy. Novel Approaches and Strategies for Biologics, Vaccines and Cancer Therapies. Elsevier; 2015: 15-39.

[10] Bottai G, Truffi M, Corsi F, Santarpia L. Progress in nonviral gene therapy for breast cancer and what comes next? Expert Opin Biol Ther. 2017; 17(5): 595-611.

[11] Li C, Samulski RJ. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020; 21(4): 255-272.

[12] Drag S, Dotiwala F, Upadhyay AK. Gene therapy for retinal degenerative diseases: progress, challenges, and future directions. Invest Ophthalmol Vis Sci. 2023; 64(7): 39-39.

[13] Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097): 849-860.

[14] Fischer MD, Ochakovski GA, Beier B, et al. Efficacy and safety of retinal gene therapy using adeno-associated virus vector for patients with choroideremia: a randomized clinical trial. JAMA Ophthalmol. 2019; 137(11): 1247-1254.

[15] Borel F, Kay MA, Mueller C. Recombinant AAV as a platform for translating the therapeutic potential of RNA interference. Mol Ther. 2014; 22(4): 692-701.

[16] Abudayyeh OO, Gootenberg JS, Essletzbichler P, et al. RNA targeting with CRISPR–Cas13. Nature. 2017; 550(7675): 280-284.

[17] Thakore PI, Kwon JB, Nelson CE, et al. RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors. Nat Commun. 2018; 9(1): 1674.

[18] Jiang J, Zhang X, Tang Y, Li S, Chen J. Progress on ocular siRNA gene-silencing therapy and drug delivery systems. Fundam Clin Pharmacol. 2021; 35(1): 4-24.

[19] Naik S, Shreya AB, Raychaudhuri R, et al. Small interfering RNAs (siRNAs) based gene silencing strategies for the treatment of glaucoma: recent advancements and future perspectives. Life Sci. 2021; 264: 118712.

[20] Yang Q, Zhang C, Xie H, et al. Silencing Nogo-B improves the integrity of blood-retinal barrier in diabetic retinopathy via regulating Src, PI3K/Akt and ERK pathways. Biochem Biophys Res Commun. 2021; 581: 96-102.

[21] Wang D, Tai PW, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019; 18(5): 358-378.

[22] Hocquemiller M, Giersch L, Audrain M, Parker S, Cartier N. Adeno-associated virus-based gene therapy for CNS diseases. Hum Gene Ther. 2016; 27(7): 478-496.

[23] Zingg B, Chou X-l, Zhang Z-g, et al. AAV-mediated anterograde transsynaptic tagging: mapping corticocollicular input-defined neural pathways for defense behaviors. Neuron. 2017; 93(1): 33-47.

[24] Gardner MR, Kattenhorn LM, Kondur HR, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015; 519(7541): 87-91.

[25] Kim H, Kim J-S. A guide to genome engineering with programmable nucleases. Nat Rev Genet. 2014; 15(5): 321-334.

[26] Liu G, Lin Q, Jin S, Gao C. The CRISPR-Cas toolbox and gene editing technologies. Mol Cell. 2022; 82(2): 333-347.

[27] Azhagiri MKK, Babu P, Venkatesan V, Thangavel S. Homology-directed gene-editing approaches for hematopoietic stem and progenitor cell gene therapy. Stem Cell Res Ther. 2021; 12(1): 1-12.

[28] Kleinstiver BP, Prew MS, Tsai SQ, et al. Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition. Nat Biotechnol. 2015; 33(12): 1293-1298.

[29] Zhang F. Development of CRISPR-Cas systems for genome editing and beyond. Quarterly Rev Biophys. 2019; 52: e6.

[30] Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020; 38(7): 824-844.

[31] Garcia-Doval C, Jinek M. Molecular architectures and mechanisms of Class 2 CRISPR-associated nucleases. Curr Opin Struct Biol. 2017; 47: 157-166.

[32] Zafra MP, Schatoff EM, Katti A, et al. Optimized base editors enable efficient editing in cells, organoids and mice. Nat Biotechnol. 2018; 36(9): 888-893.

[33] Liu Z, Lu Z, Yang G, et al. Efficient generation of mouse models of human diseases via ABE-and BE-mediated base editing. Nat Commun. 2018; 9(1): 2338.

[34] Liu Z, Chen M, Chen S, et al. Highly efficient RNA-guided base editing in rabbit. Nat Commun. 2018; 9(1): 2717.

[35] Song C-Q, Jiang T, Richter M, et al. Adenine base editing in an adult mouse model of tyrosinaemia. Nat Biomed Eng. 2020; 4(1): 125-130.

[36] Porto EM, Komor AC, Slaymaker IM, Yeo GW. Base editing: advances and therapeutic opportunities. Nat Rev Drug Discov. 2020; 19(12): 839-859.

[37] Komor AC, Zhao KT, Packer MS, et al. Improved base excision repair inhibition and bacteriophage Mu Gam protein yields C: g-to-T: a base editors with higher efficiency and product purity. Sci Adv. 2017; 3(8): eaao4774.

[38] Koblan LW, Doman JL, Wilson C, et al. Improving cytidine and adenine base editors by expression optimization and ancestral reconstruction. Nat Biotechnol. 2018; 36(9): 843-846.

[39] Thuronyi BW, Koblan LW, Levy JM, et al. Continuous evolution of base editors with expanded target compatibility and improved activity. Nat Biotechnol. 2019; 37(9): 1070-1079.

[40] Villiger L, Grisch-Chan HM, Lindsay H, et al. Treatment of a metabolic liver disease by in vivo genome base editing in adult mice. Nat Med. 2018; 24(10): 1519-1525.

[41] Levy JM, Yeh W-H, Pendse N, et al. Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses. Nat Biomed Eng. 2020; 4(1): 97-110.

[42] Davis JR, Wang X, Witte IP, et al. Efficient in vivo base editing via single adeno-associated viruses with size-optimized genomes encoding compact adenine base editors. Nat Biomed Eng. 2022; 6(11): 1272-1283.

[43] Silva-Pinheiro P, Nash PA, Van Haute L, Mutti CD, Turner K, Minczuk M. In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue. Nat Commun. 2022; 13(1): 750.

[44] Merkle T, Merz S, Reautschnig P, et al. Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides. Nat Biotechnol. 2019; 37(2): 133-138.

[45] Qu L, Yi Z, Zhu S, et al. Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs. Nat Biotechnol. 2019; 37(9): 1059-1069.

[46] Cox DB, Gootenberg JS, Abudayyeh OO, et al. RNA editing with CRISPR-Cas13. Science. 2017; 358(6366): 1019-1027.

[47] Abudayyeh OO, Gootenberg JS, Franklin B, et al. A cytosine deaminase for programmable single-base RNA editing. Science. 2019; 365(6451): 382-386.

[48] Anzalone AV, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019; 576(7785): 149-157.

[49] Sürün D, Schneider A, Mircetic J, et al. Efficient generation and correction of mutations in human iPS cells utilizing mRNAs of CRISPR base editors and prime editors. Genes. 2020; 11(5): 511.

[50] Liu Y, Li X, He S, et al. Efficient generation of mouse models with the prime editing system. Cell Discov. 2020; 6(1): 27.

[51] Gao P, Lyu Q, Ghanam AR, et al. Prime editing in mice reveals the essentiality of a single base in driving tissue-specific gene expression. Genome Biol. 2021; 22(1): 1-21.

[52] Chen PJ, Hussmann JA, Yan J, et al. Enhanced prime editing systems by manipulating cellular determinants of editing outcomes. Cell. 2021; 184(22): 5635-5652. e29.

[53] Zheng C, Liang S-Q, Liu B, et al. A flexible split prime editor using truncated reverse transcriptase improves dual-AAV delivery in mouse liver. Mol Ther. 2022; 30(3): 1343-1351.

[54] Liu B, Dong X, Cheng H, et al. A split prime editor with untethered reverse transcriptase and circular RNA template. Nat Biotechnol. 2022; 40(9): 1388-1393.

[55] Liang X, Potter J, Kumar S, Ravinder N, Chesnut JD. Enhanced CRISPR/Cas9-mediated precise genome editing by improved design and delivery of gRNA, Cas9 nuclease, and donor DNA. J Biotechnol. 2017; 241: 136-146.

[56] Scholefield J, Harrison PT. Prime editing–an update on the field. Gene Ther. 2021; 28(7-8): 396-401.

[57] Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018; 359(6372).

[58] Yan N, Feng H, Sun Y, et al. Cytosine base editors induce off-target mutations and adverse phenotypic effects in transgenic mice. Nat Commun. 2023; 14(1): 1784.

[59] Zabaleta N, Unzu C, Weber ND, Gonzalez-Aseguinolaza G. Gene therapy for liver diseases—progress and challenges. Nat Rev Gastroenterol Hepatol. 2023: 1-18.

[60] Bordet T, Behar-Cohen F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov Today. 2019; 24(8): 1685-1693.

[61] Tian B, Bilsbury E, Doherty S, et al. Ocular drug delivery: advancements and innovations. Pharmaceutics. 2022; 14(9): 1931.

[62] Craigie R, Bushman FD. Host factors in retroviral integration and the selection of integration target sites. Mobile DNA III. 2015: 1035-1050.

[63] Ghosh S, Brown AM, Jenkins C, Campbell K. Viral vector systems for gene therapy: a comprehensive literature review of progress and biosafety challenges. Appl Biosaf. 2020; 25(1): 7-18.

[64] Lesbats P, Engelman AN, Cherepanov P. Retroviral DNA integration. Chem Rev. 2016; 116(20): 12730-12757.

[65] Lundstrom K. Viral vectors in gene therapy: where do we stand in 2023? Viruses. 2023; 15(3): 698.

[66] Sakuma T, Barry MA, Ikeda Y. Lentiviral vectors: basic to translational. Biochem J. 2012; 443(3): 603-618.

[67] Escors D, Breckpot K. Lentiviral vectors in gene therapy: their current status and future potential. Arch Immunol Ther Exp (Warsz). 2010; 58: 107-119.

[68] Kalesnykas G, Kokki E, Alasaarela L, et al. Comparative study of adeno-associated virus, adenovirus, Bacu lovirus and Lentivirus vectors for gene therapy of the eyes. Curr Gene Ther. 2017; 17(3): 235-247.

[69] Campochiaro PA, Lauer AK, Sohn EH, et al. Lentiviral vector gene transfer of endostatin/angiostatin for macular degeneration (GEM) study. Hum Gene Ther. 2017; 28(1): 99-111.

[70] Berk A. In: Knipe DM & Howley MP, eds. Fields Virology. Lippincott Williams & Wilkins, Philadelphia; 2007: 2355-2436.

[71] Chang J. Adenovirus vectors: excellent tools for vaccine development. Immune Netw. 2021; 21(1): e6.

[72] Watanabe M, Nishikawaji Y, Kawakami H, Kosai K-i. Adenovirus biology, recombinant adenovirus, and adenovirus usage in gene therapy. Viruses. 2021; 13(12): 2502.

[73] SM Wold W, Toth K. Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther. 2013; 13(6): 421-433.

[74] JT S, Wam B, Ac B, Sa N. Adenoviral vectors for cardiovascular gene therapy applications: a clinical and industry perspective. J Mol Med. 2022; 100(6): 875-901.

[75] Sadoff J, Gray G, Vandebosch A, et al. Safety and efficacy of single-dose Ad26. COV2. S vaccine against Covid-19. N Engl J Med. 2021; 384(23): 2187-2201.

[76] Mingozzi F, High KA. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood. 2013; 122(1): 23-36.

[77] Koponen S, Kokki E, Kinnunen K, Ylä-Herttuala S. Viral-vector-delivered anti-angiogenic therapies to the eye. Pharmaceutics. 2021; 13(2): 219.

[78] Palmer DJ, Turner DL, Ng P. A single “all-in-one” helper-dependent adenovirus to deliver donor DNA and CRISPR/Cas9 for efficient homology-directed repair. Mol Ther Methods Clin Dev. 2020; 17: 441-447.

[79] Lino CA, Harper JC, Carney JP, Timlin JA. Delivering CRISPR: a review of the challenges and approaches. Drug Deliv. 2018; 25(1): 1234-1257.

[80] Maurer AC, Weitzman MD. Adeno-associated virus genome interactions important for vector production and transduction. Hum Gene Ther. 2020; 31(9-10): 499-511.

[81] Berns KI. The unusual properties of the AAV inverted terminal repeat. Hum Gene Ther. 2020; 31(9-10): 518-523.

[82] Drouin LM, Agbandje-McKenna M. Adeno-associated virus structural biology as a tool in vector development. Future Virol. 2013; 8(12): 1183-1199.

[83] Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs. Mol Ther. 2021; 29(2): 464-488.

[84] Barnes LF, Draper BE, Chen Y-T, Powers TW, Jarrold MF. Quantitative analysis of genome packaging in recombinant AAV vectors by charge detection mass spectrometry. Mol Ther Methods Clin Dev. 2021; 23: 87-97.

[85] Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: a long journey to successful gene transfer. Mol Ther. 2020; 28(3): 723-746.

[86] Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther. 2020; 28(3): 709-722.

[87] Recchia A. AAV-CRISPR persistence in the eye of the beholder. Mol Ther. 2019; 27(1): 12-14.

[88] Al Qtaish N, Gallego I, Villate-Beitia I, et al. Niosome-based approach for in situ gene delivery to retina and brain cortex as immune-privileged tissues. Pharmaceutics. 2020; 12(3): 198.

[89] Pilipenko I, Korzhikov-Vlakh V, Sharoyko V, et al. pH-sensitive chitosan–heparin nanoparticles for effective delivery of genetic drugs into epithelial cells. Pharmaceutics. 2019; 11(7): 317.

[90] Osipova O, Sharoyko V, Zashikhina N, et al. Amphiphilic polypeptides for VEGF siRNA delivery into retinal epithelial cells. Pharmaceutics. 2020; 12(1): 39.

[91] Panchal SS, Vasava DV. Synthetic biodegradable polymeric materials in non-viral gene delivery. Int J Polym Mater Polym Biomater. 2023: 1-12.

[92] Guo Z, Lin L, Chen J, et al. Poly (ethylene glycol)-poly-l-glutamate complexed with polyethyleneimine– polyglycine for highly efficient gene delivery in vitro and in vivo. Biomater Sci. 2018; 6(11): 3053-3062.

[93] O’Keeffe Ahern J, Lara-Sáez I, Zhou D, et al. Non-viral delivery of CRISPR–Cas9 complexes for targeted gene editing via a polymer delivery system. Gene Ther. 2022; 29(3-4): 157-170.

[94] Li L, Yang Z, Zhu S, et al. A RAtionally Designed Semiconducting Polymer Brush for NIR-II imaging-guided light-triggered remote control of CRISPR/Cas9 genome editing. Advanced Materials. 2019; 31(21): 1901187.

[95] Milani P, Mussinelli R, Perlini S, Palladini G, Obici L. An evaluation of patisiran: a viable treatment option for transthyretin-related hereditary amyloidosis. Expert Opin Pharmacother. 2019; 20(18): 2223-2228.

[96] Rosenblum D, Gutkin A, Kedmi R, et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci Adv. 2020; 6(47): eabc9450.

[97] Zhang Y, Iaffaldano B, Qi Y. CRISPR ribonucleoprotein-mediated genetic engineering in plants. Plant Commun. 2021; 2(2): 100168.

[98] Kim K, Park SW, Kim JH, et al. Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Genome Res. 2017; 27(3): 419-426.

[99] Banskota S, Raguram A, Suh S, et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell. 2022; 185(2): 250-265. e16.

[100] Jang H-K, Jo DH, Lee S-N, et al. High-purity production and precise editing of DNA base editing ribonucleoproteins. Sci Adv. 2021; 7(35): eabg2661.

[101] Duan L, Xu L, Xu X, et al. Exosome-mediated delivery of gene vectors for gene therapy. Nanoscale. 2021; 13(3): 1387-1397.

[102] Cross N, van Steen C, Zegaoui Y, Satherley A, Angelillo L. Retinitis pigmentosa: burden of disease and current unmet needs. Clin Ophthalmol. 2022: 1993-2010.

[103] Newton F, Megaw R. Mechanisms of photoreceptor death in retinitis pigmentosa. Genes. 2020; 11(10): 1120.

[104] Xu M, Zhai Y, MacDonald IM. Visual field progression in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2020; 61(6): 56-56.

[105] Aït-Ali N, Fridlich R, Millet-Puel G, et al. Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell. 2015; 161(4): 817-832.

[106] Yu H-G. Retinitis pigmentosa. Inherited Retinal Disease. Springer; 2022: 69-97.

[107] Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006; 368(9549): 1795-1809.

[108] Vajter M, Kousal B, Moravikova J, et al. Leber congenital amaurosis and early onset severe retinal dystrophy in the Czech Republic: mutational spectrum and clinical findings. Acta Ophthalmol (Copenh). 2022; 100(S275).

[109] Kondkar AA, Abu-Amero KK. Leber congenital amaurosis: current genetic basis, scope for genetic testing and personalized medicine. Exp Eye Res. 2019; 189: 107834.

[110] Delmaghani S, El-Amraoui A. The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification. Hum Genet. 2022; 141(3-4): 709-735.

[111] Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097): 849-860.

[112] Liu W, Liu S, Li P, Yao K. Retinitis pigmentosa: progress in molecular pathology and biotherapeutical strategies. Int J Mol Sci. 2022; 23(9): 4883.

[113] Martinez-Fernandez De La Camara C, Nanda A, Salvetti AP, Fischer MD, MacLaren RE. Gene therapy for the treatment of X-linked retinitis pigmentosa. Exp Opin Orphan Drugs. 2018; 6(3): 167-177.

[114] Hu S, Du J, Chen N, et al. In vivo CRISPR/Cas9-mediated genome editing mitigates photoreceptor degeneration in a mouse model of X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2020; 61(4): 31-31.

[115] Gumerson JD, Alsufyani A, Yu W, et al. Restoration of RPGR expression in vivo using CRISPR/Cas9 gene editing. Gene Ther. 2022; 29(1-2): 81-93.

[116] Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med. 2020; 26(3): 354-359.

[117] Deng Y, Qiao L, Du M, et al. Age-related macular degeneration: epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes Dis. 2022; 9(1): 62-79.

[118] Fine SL, Berger JW, Maguire MG, Ho AC. Age-related macular degeneration. N Engl J Med. 2000; 342(7): 483-492.

[119] Fritsche LG, Fariss RN, Stambolian D, Abecasis GR, Curcio CA, Swaroop A. Age-related macular degeneration: genetics and biology coming together. Ann Rev Genom Hum Genet. 2014; 15: 151-171.

[120] Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720): 385-389.

[121] DeAngelis MM, Ji F, Adams S, et al. Alleles in the HtrA serine peptidase 1 gene alter the risk of neovascular age-related macular degeneration. Ophthalmology. 2008; 115(7): 1209-1215. e7.

[122] Li C-M, Clark ME, Chimento MF, Curcio CA. Apolipoprotein localization in isolated drusen and retinal apolipoprotein gene expression. Invest Ophthalmol Vis Sci. 2006; 47(7): 3119-3128.

[123] Gliem M, Müller PL, Mangold E, et al. Sorsby fundus dystrophy: novel mutations, novel phenotypic characteristics, and treatment outcomes. Invest Ophthalmol Vis Sci. 2015; 56(4): 2664-2676.

[124] Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci USA. 2010; 107(16): 7395-7400.

[125] Reichel E, Berrocal AM, Ip M, et al. Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration. Ophthalmology. 1999; 106(10): 1908-1914.

[126] Nowak-Sliwinska P, Van Den Bergh H, Sickenberg M, Koh AH. Photodynamic therapy for polypoidal choroidal vasculopathy. Prog Retin Eye Res. 2013; 37: 182-199.

[127] Group VISiONCT. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006; 113(9): 1508.e1–1508.e25.

[128] Chong V. Ranibizumab for the treatment of wet AMD: a summary of real-world studies. Eye. 2016; 30(2): 270-286.

[129] Sarwar S, Clearfield E, Soliman MK, et al. Aflibercept for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2016; 2(2): CD011346.

[130] Li X, Xu G, Wang Y, et al. Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: aURORA study. Ophthalmology. 2014; 121(9): 1740-1747.

[131] Heier JS, Kherani S, Desai S, 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(10089): 50-61.

[132] Heier JS, Kherani S, Desai S, 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(10089): 50-61.

[133] Grishanin R, Vuillemenot B, Sharma P, et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Mol Ther. 2019; 27(1): 118-129.

[134] Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression. J Clin Investig. 2019; 129(11): 4901-4911.

[135] Li Y, Alhendi AM, Yeh M-C, et al. Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis. Sci Adv. 2020; 6(31): eaaz7815.

[136] Dreismann AK, McClements ME, Barnard AR, et al. Functional expression of complement factor I following AAV-mediated gene delivery in the retina of mice and human cells. Gene Ther. 2021; 28(5): 265-276.

[137] Qi X, Francelin C, Mitter S, et al. β-secretase 1 overexpression by AAV-mediated gene delivery prevents retina degeneration in a mouse model of age-related macular degeneration. Mol Ther. 2023; 31(7): 2042-2055.

[138] Koenekoop RK. The gene for Stargardt disease, ABCA4, is a major retinal gene: a mini-review. Ophthalmic Genet. 2003; 24(2): 75-80.

[139] Muller A, Sullivan J, Schwarzer W, et al. High-efficiency base editing for Stargardt disease in mice, non-human primates, and human retina tissue. bioRxiv. 2023. 2023.04.17.535579.

[140] Mehat MS, Sundaram V, Ripamonti C, et al. Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells in macular degeneration. Ophthalmology. 2018; 125(11): 1765-1775.

[141] Cheng H, Khan NW, Roger JE, Swaroop A. Excess cones in the retinal degeneration rd7 mouse, caused by the loss of function of orphan nuclear receptor Nr2e3, originate from early-born photoreceptor precursors. Hum Mol Genet. 2011; 20(21): 4102-4115.

[142] Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res. 2012; 31(3): 195-212.

[143] Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery. Mol Ther. 2018; 26(9): 2282-2294.

[144] Fenner BJ, Russell JF, Drack AV, et al. Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials. Front Med. 2023; 10: 1204095.

[145] García-García GP, Martínez-Rubio M, Moya-Moya M-A, Pérez-Santonja J, Escribano J. Current perspectives in Bietti crystalline dystrophy. Clin Ophthalmol. 2019: 1379-1399.

[146] Sarkar H, Moosajee M. Choroideremia: molecular mechanisms and therapies. Trends Mol Med. 2022; 28(5): 378-387.

[147] Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018; 24(10): 1507-1512.

[148] Fischer MD, Ochakovski GA, Beier B, et al. Changes in retinal sensitivity after gene therapy in choroideremia. Retina. 2020; 40(1): 160-168.

[149] Aleman TS, Huckfeldt RM, Serrano LW, et al. Adeno-Associated virus serotype 2–hCHM subretinal delivery to the macula in choroideremia: two-year interim results of an ongoing phase I/II gene therapy trial. Ophthalmology. 2022; 129(10): 1177-1191.

[150] Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol. 2015; 9: 1165-1176.

[151] Manickam AH, Michael MJ, Ramasamy S. Mitochondrial genetics and therapeutic overview of Leber’s hereditary optic neuropathy. Indian J Ophthalmol. 2017; 65(11): 1087-1092.

[152] Carelli V, Newman NJ, Yu-Wai-Man P, et al. Indirect comparison of lenadogene nolparvovec gene therapy versus natural history in patients with leber hereditary optic neuropathy carrying the m.11778G>A MT-ND4 mutation. Ophthalmol Ther. 2023; 12(1): 401-429.

[153] Lam BL, Feuer WJ, Davis JL, et al. Leber hereditary optic neuropathy gene therapy: adverse events and visual acuity results of all patient groups. Am J Ophthalmol. 2022; 241: 262-271.

[154] Burghes AH, Beattie CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci. 2009; 10(8): 597-609.

[155] Wijaya YOS, Rohmah MA, Niba ETE, et al. Phenotypes of SMA patients retaining SMN1 with intragenic mutation. Brain Dev. 2021; 43(7): 745-758.

[156] Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017; 81(3): 355-368.

[157] Sumner CJ, Crawford TO. Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. J Clin Investig. 2018; 128(8): 3219-3227.

[158] Mercuri E, Pera MC, Scoto M, Finkel R, Muntoni F. Spinal muscular atrophy—insights and challenges in the treatment era. Nat Rev Neurol. 2020; 16(12): 706-715.

[159] Foust KD, Wang X, McGovern VL, et al. Retracted article: rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010; 28(3): 271-274.

[160] Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017; 377(18): 1713-1722.

[161] Koenig M, Hoffman E, Bertelson C, Monaco A, Feener C, Kunkel L. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987; 50(3): 509-517.

[162] Brooke M, Griggs R, Mendell JR, Fenichel G, Shumate J. The natural history of Duchenne muscular dystrophy: a caveat for therapeutic trials. Trans Am Neurol Assoc. 1981; 106: 195-199.

[163] Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74. MHCK7. micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. 2020; 77(9): 1122-1131.

[164] Mendell JR, Shieh PB, McDonald CM, et al. Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. Front Cell Dev Biol. 2023; 11: 1167762.

[165] Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther. 2018; 26(10): 2337-2356.

[166] Annoussamy M, Lilien C, Gidaro T, et al. X-linked myotubular myopathy: a prospective international natural history study. Neurology. 2019; 92(16): e1852-e1867.

[167] Hnia K, Vaccari I, Bolino A, Laporte J. Myotubularin phosphoinositide phosphatases: cellular functions and disease pathophysiology. Trends Mol Med. 2012; 18(6): 317-327.

[168] Gómez-Oca R, Cowling BS, Laporte J. Common pathogenic mechanisms in centronuclear and myotubular myopathies and latest treatment advances. Int J Mol Sci. 2021; 22(21): 11377.

[169] Shieh P, Kuntz N, Dowling J, et al. OP018: aSPIRO gene therapy trial in X-linked myotubular myopathy (XLMTM): update on preliminary efficacy and safety findings. Genet Med. 2022; 24(3): S350.

[170] Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science. 2018; 359(6372): eaan4672.

[171] Hudry E, Vandenberghe LH. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron. 2019; 101(5): 839-862.

[172] Giau VV, Lee H, Shim KH, Bagyinszky E, An SSA. Genome-editing applications of CRISPR–Cas9 to promote in vitro studies of Alzheimer’s disease. Clin Interv Aging. 2018: 221-233.

[173] Rafii MS, Baumann TL, Bakay RA, et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimer’s Dement. 2014; 10(5): 571-581.

[174] LeWitt PA, Rezai AR, Leehey MA, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011; 10(4): 309-319.

[175] Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet. 2007; 369(9579): 2097-2105.

[176] Marks WJ, Bartus RT, Siffert J, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010; 9(12): 1164-1172.

[177] Beaudin M, Manto M, Schmahmann JD, Pandolfo M, Dupre N. Recessive cerebellar and afferent ataxias—clinical challenges and future directions. Nat Rev Neurol. 2022; 18(5): 257-272.

[178] Leone P, Shera D, McPhee SW, et al. Long-term follow-up after gene therapy for canavan disease. Sci Transl Med. 2012; 4(165): 165ra163-165ra163.

[179] Hwu W-L, Chien Y-H, Lee N-C, Li M-H, Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep. 2018;40: 1-6.

[180] Chien Y-H, Lee N-C, Tseng S-H, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017; 1(4): 265-273.

[181] Hwu PW-L, Pachelli P, Chien Y, et al. Safety and improved efficacy outcomes in children with AADC deficiency treated with eladocagene exuparvovec gene therapy: results from three clinical trials. Cytotherapy. 2021; 23(4): 33.

[182] Tai C-H, Lee N-C, Chien Y-H, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022; 30(2): 509-518.

[183] Castaman G, Matino D. Hemophilia A and B: molecular and clinical similarities and differences. Haematologica. 2019; 104(9): 1702.

[184] Nienhuis AW, Nathwani AC, Davidoff AM. Gene therapy for hemophilia. Mol Ther. 2017; 25(5): 1163-1167.

[185] Rangarajan S, Walsh L, Lester W, et al. AAV5–factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017; 377(26): 2519-2530.

[186] Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020; 382(1): 29-40.

[187] Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022; 386(11): 1013-1025.

[188] George LA, Monahan PE, Eyster ME, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia A. N Engl J Med. 2021; 385(21): 1961-1973.

[189] Pipe SW, Ferrante F, Reis M, et al. First-in-human gene therapy study of AAVhu37 capsid vector technology in severe hemophilia A-BAY 2599023 has broad patient eligibility and stable and sustained long-term expression of FVIII. Blood. 2020; 136: 44-45.

[190] Goodeve AC. Hemophilia B: molecular pathogenesis and mutation analysis. J Thromb Haemost. 2015; 13(7): 1184-1195.

[191] Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing “empty viral particles” on safety and efficacy of gene transfer. Blood. 2018; 132: 491.

[192] Pipe SW, Leebeek FW, Recht M, et al. Gene therapy with etranacogene dezaparvovec for hemophilia B. N Engl J Med. 2023; 388(8): 706-718.

[193] Chowdary P, Shapiro S, Makris M, et al. Phase 1–2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022; 387(3): 237-247.

[194] Tanai E, Frantz S. Pathophysiology of heart failure. Comprehens Physiol. 2011; 6(1): 187-214.

[195] Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016; 13(6): 368-378.

[196] Ralapanawa U, Sivakanesan R. Epidemiology and the magnitude of coronary artery disease and acute coronary syndrome: a narrative review. J Epidemiol Global Health. 2021; 11(2): 169.

[197] Korpela H, Järveläinen N, Siimes S, et al. Gene therapy for ischaemic heart disease and heart failure. J Intern Med. 2021; 290(3): 567-582.

[198] Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016; 387(10024): 1178-1186.

[199] Hulot J-S, Ishikawa K, Hajjar RJ. Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J. 2016; 37(21): 1651-1658.

[200] Hammond HK, Penny WF, Traverse JH, et al. Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: a randomized clinical trial. JAMA Cardiol. 2016; 1(2): 163-171.

[201] Timmis A, Townsend N, Gale CP, et al. European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J. 2020; 41(1): 12-85.

[202] Ylä-Herttuala S, Baker AH. Cardiovascular gene therapy: past, present, and future. Mol Ther. 2017; 25(5): 1095-1106.

[203] Zhou Y, Zhu X, Cui H, et al. The role of the VEGF family in coronary heart disease. Front Cardiovasc Med. 2021; 8: 738325.

[204] Hartikainen J, Hassinen I, Hedman A, et al. Adenoviral intramyocardial VEGF-DΔNΔC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017; 38(33): 2547-2555.

[205] Leikas AJ, Hassinen I, Hedman A, Kivelä A, Ylä-Herttuala S, Hartikainen JE. Long-term safety and efficacy of intramyocardial adenovirus-mediated VEGF-DΔNΔC gene therapy eight-year follow-up of phase I KAT301 study. Gene Ther. 2022; 29(5): 289-293.

[206] Povsic TJ, Henry TD, Traverse JH, et al. EXACT trial: results of the phase 1 dose-escalation study. Circ Cardiovasc Interv. 2023; 16(8): e012997.

[207] Shaimardanova AA, Solovyeva VV, Issa SS, Rizvanov AA. Gene therapy of sphingolipid metabolic disorders. Int J Mol Sci. 2023; 24(4): 3627.

[208] Rha AK, Maguire AS, Martin DR. GM1 gangliosidosis: mechanisms and management. Appl Clin Genet. 2021: 209-233.

[209] Lowes LP, Alfano LN, Arnold WD, et al. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr Neurol. 2019; 98: 39-45.

[210] Solovyeva VV, Shaimardanova AA, Chulpanova DS, Kitaeva KV, Chakrabarti L, Rizvanov AA. New approaches to Tay-Sachs disease therapy. Front Physiol. 2018; 9: 1663.

[211] Hughes DA, Patel N, Kinch R, et al. First-in-human study of a liver-directed AAV gene therapy (FLT190) in Fabry disease. Mol Genet Metab. 2020; 129(2): S77-S78.

[212] Nguyen Y, Stirnemann J, Belmatoug N. Gaucher disease: a review. La Revue de medecine interne. 2019; 40(5): 313-322.

[213] Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014; 370(10): 901-910.

[214] Harmatz P, Prada CE, Burton BK, et al. First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B. Mol Ther. 2022; 30(12): 3587-3600.

[215] Tsuchida CA, Brandes N, Bueno R, et al. Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells. Cell. 2023; 186(21): 4567-4582. e20.

[216] Chan YK, Dick AD, Hall SM, Langmann T, Scribner CL, Mansfield BC. Inflammation in viral vector-mediated ocular gene therapy: a review and report from a workshop hosted by the foundation fighting blindness, 9/2020. Transl Vis Sci Technol. 2021; 10(4): 3.

[217] Ghoraba HH, Akhavanrezayat A, Karaca I, et al. Ocular gene therapy: a literature review with special focus on immune and inflammatory responses. Clin Ophthalmol. 2022; 16: 1753-1771.

[218] Xiong W, Wu DM, Xue Y, et al. AAV cis-regulatory sequences are correlated with ocular toxicity. Proc Natl Acad Sci USA. 2019; 116(12): 5785-5794.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.