Adeno-associated virus as a delivery vector for gene therapy of human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 2, 2024

Abstract Adeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability establish long-term expression different tissues. Recombinant AAV (rAAV) been engineered for enhanced specificity developed treating various diseases. However, rAAV is being more widely used therapy, the increased demand created challenges existing manufacturing methods. Seven rAAV-based products have received regulatory approval, but there continue be concerns about safely using high-dose viral therapies humans, including immune responses adverse effects such genotoxicity, hepatotoxicity, thrombotic microangiopathy, neurotoxicity. In this review, we explore biology with an emphasis on current vector engineering strategies technologies. We discuss how rAAVs are employed ongoing trials ocular, neurological, metabolic, hematological, neuromuscular, cardiovascular diseases well cancers. outline triggered by rAAV, address associated side effects, mitigate these reactions. hope that discussing recent advancements field will helpful guide researchers clinicians navigating ever-evolving landscape of therapy.

Language: Английский

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Advances in gene therapy hold promise for treating hereditary hearing loss

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(4), P. 934 - 950

Published: Feb. 8, 2023

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing reconstructing material, thus being expected be the most promising strategy for disorders. Due growing attention hearing impairment, an increasing amount of research is attempting utilize gene hereditary loss (HHL), important monogenic disease and common type congenital deafness. Several clinical trials HHL have recently been approved, and, additionally, CRISPR-Cas tools attempted treatment. Therefore, in order further advance development inner ear promote its broad application other forms disease, it imperative review progress HHL. Herein, we address three main strategies (gene replacement, suppression, editing), summarizing that appropriate particular based different pathogenic mechanisms, then focusing their successful applications preclinical trials. Finally, elaborate challenges outlooks

Language: Английский

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Deafness: from genetic architecture to gene therapy

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 24(10), P. 665 - 686

Published: May 12, 2023

Language: Английский

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Towards the Clinical Application of Gene Therapy for Genetic Inner Ear Diseases

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(3), P. 1046 - 1046

Published: Jan. 29, 2023

Hearing loss, the most common human sensory defect worldwide, is a major public health problem. About 70% of congenital forms and 25% adult-onset deafness are genetic origin. In total, 136 genes have already been identified there thought to be several hundred more awaiting identification. However, currently no cure for sensorineural deafness. recent years, translational research studies shown gene therapy effective against inherited inner ear diseases, application this technology humans now within reach. We provide here comprehensive practical overview current advances in deafness, with without an associated vestibular defect. focus on different approaches, considering their prospects, including viral vector used, delivery route. also discuss clinical various strategies, strengths, weaknesses, challenges overcome.

Language: Английский

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Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

Advanced Science, Journal Year: 2023, Volume and Issue: 11(3)

Published: Nov. 28, 2023

Abstract OTOF mutations are the principal causes of auditory neuropathy. There reports on Otof ‐related gene therapy in mice, but there is no preclinical research drug evaluations. Here, Anc80L65 and mouse hair cell‐specific Myo15 promoter (mMyo15) used to selectively effectively deliver human cells mice nonhuman primates evaluate efficacy safety drugs. A new dual‐AAV ‐OTOF‐ hybrid strategy transfer full‐length generated, which can stably restore hearing adult p.Q939*/Q939* with profound deafness, longest duration being at least 150 days, best therapeutic effect without difference from wild‐type mice. An AAV microinjection method into cochlea cynomolgus monkeys impairment further established found be safely driven by mMyo15 cells. In addition, dose drugs has impact normal does not cause significant systemic toxicity both primates. summary, this study develops a potential for DFNB9 patients clinic provides complete, standardized, systematic data clinical application.

Language: Английский

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The menace of severe adverse events and deaths associated with viral gene therapy and its potential solution

Medicinal Research Reviews, Journal Year: 2024, Volume and Issue: 44(5), P. 2112 - 2193

Published: March 28, 2024

Abstract Over the past decade, in vivo gene replacement therapy has significantly advanced, resulting market approval of numerous therapeutics predominantly relying on adeno‐associated viral vectors (AAV). While have undeniably addressed several critical healthcare challenges, their clinical application unveiled a range limitations and safety concerns. This review highlights emerging challenges field therapy. At first, we discuss both role biological barriers with focus AAVs, current landscape human We delineate advantages disadvantages AAVs as delivery vehicles, mostly from perspective (hepatotoxicity, cardiotoxicity, neurotoxicity, inflammatory responses etc.), outline mechanisms adverse events response to AAV. Contribution every aspect AAV (genomic structure, capsid proteins) host injected is considered substantiated by basic, translational studies. The updated evaluation recent trials medical experience clearly shows risks that sometimes overshadow hopes for curing hereditary disease. last, set established new molecular nanotechnology tools approaches are provided potential solutions mitigating or eliminating side effects. increasing number severe reactions and, sadly deaths, demands decisive actions resolve issue immune extremely high doses used In these various strategies under development, including aimed at augmenting characteristics others focused creating secure efficacious non‐viral vectors. comprehensive offers an overarching present state utilizing

Language: Английский

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AAV‐mediated Gene Therapy for Hereditary Deafness: Progress and Perspectives

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 18, 2024

Abstract Hereditary deafness is the most prevalent sensory deficit disorder, with over 100 identified deafness‐related genes. Clinical treatment options are currently limited to external devices like hearing aids and cochlear implants. Gene therapy has shown promising results in various genetic disorders emerged as a potential for hereditary deafness. It successfully restored function >20 types of model mice can almost completely cure patients autosomal recessvie 9 (DFNB9) caused by OTOFERLIN ( OTOF ) mutation, thus serving translational paradigm gene other forms However, due complexity inner ear structure, diverse nature genes, variations transduction efficiency among different cells targeted adeno‐associated virus (AAV), precision approaches required This review provides comprehensive overview deafness, including preclinical studies recent research advancements this field well challenges associated AAV‐mediated therapy.

Language: Английский

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Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates

Molecular Therapy — Methods & Clinical Development, Journal Year: 2023, Volume and Issue: 31, P. 101154 - 101154

Published: Nov. 10, 2023

Language: Английский

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Cochlear transduction via cerebrospinal fluid delivery of AAV in non-human primates

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(3), P. 609 - 612

Published: Jan. 6, 2023

Adeno-associated viruses (AAVs) have been approved for clinical use several indications, 1 Kuzmin D.A. Shutova M.V. Johnston N.R. Smith O.P. Fedorin V.V. Kukushkin Y.S. van der Loo J.C.M. Johnstone E.C. The landscape AAV gene therapies. Nat. Rev. Drug Discov. 2021; 20: 173-174https://doi.org/10.1038/d41573-021-00017-7 Crossref PubMed Scopus (193) Google Scholar ,2 Bennett J. Maguire A.M. Lessons learned from the development of first FDA-approved therapy drug, voretigene neparvovec-rzyl. Cold Spring Harb. Perspect. Med. 2022; : a041307https://doi.org/10.1101/cshperspect.a041307 (2) with continued progress to evolve new forms improved targeting organ or cell interest. 3 Goertsen D. Goeden N. Flytzanis N.C. Gradinaru V. Targeting lung epithelium after intravenous delivery by directed evolution underexplored sites on capsid. Mol. Ther. Methods Clin. Dev. 26: 331-342https://doi.org/10.1016/j.omtm.2022.07.010 Abstract Full Text PDF (4) ,4 Gonzalez T.J. Simon K.E. Blondel L.O. Fanous M.M. Roger A.L. Maysonet M.S. Devlin G.W. Oh D.K. Havlik L.P. et al. Cross-species a highly potent variant therapeutic transfer and genome editing. Commun. 13: 5947https://doi.org/10.1038/s41467-022-33745-4 (9) ,5 Davidsson M. Wang G. Aldrin-Kirk P. Cardoso T. Nolbrant S. Hartnor Mudannayake Parmar Björklund A systematic capsid approach performed in vivo design vectors tailored properties tropism. Proc. Natl. Acad. Sci. USA. 2019; 116: 27053-27062https://doi.org/10.1073/pnas.1910061116 (90) As our laboratory is interested CNS therapies, 6 Keiser Ranum P.T. Yrigollen C.M. Carrell E.M. G.R. Muehlmatt Chen Y.H. Stein J.M. Wolf R.L. Radaelli E. Toxicity RNAi expression constructs into nonhuman primate brain. 27: 1982-1989https://doi.org/10.1038/s41591-021-01522-3 (18) we perform routine assessments transduction distribution wild-type evolved AAVs following Recently, included evaluation inner ear analyses. To surprise, observed striking cochlear hair (Figure 1, column 1) intracerebroventricular (ICV) injection AAV9.EGFP Macaca mulatta (rhesus macaque). We find that auditory cells, cells spiral ligament, limbus were transduced, most robust apex cochlea 1). There few transduced middle basal turns Upon dissection tissues similar studies evaluating an AAV9 (AAV9.KGG.mNG) CSF Chorocebus aethiops (African green) monkey, there was notable at apical upper-middle cochlea, but extensive lower-middle 2). Further, AAV1 AAV2 variants expressing different fluorophores, AAV1.RPG.mNG AAV2.HDG.mTFP, nearly all via this route administration 2, top columns AAV9.mCherry, which pooled under study, less well African green than rhesus macaque, difference potentially indicative physiological differences between two non-human (NHP) species experimental variation. 3). Because patterns AAV2.HDG.mTFP similar, confirmed mNeonGreen mTFP RNA fluorescence situ hybridization (FISH). Confocal imaging FISH probes tropism capsids bottom 1–4). Figure 2AAV1.RPG.mNG transduce Show full caption single ICV infusion AAV1.RPG.mNG, AAV9.mRuby3 male dose 3E13 total vector genomes per animal 4 years weighed 6.90 ± 0.68 kg. Columns 1–4: direct macaque cochlea. Row 1: turn. Rows 2–5: indicated tonotopic position. 6–9: analysis mTFP, mNG, mRuby3 mRNAs. derived (AAV1.RPG.mNG) had peptide insert RPGREAS aa position 590 loop 8. AAV2-derived (AAV2.HDG.mTFP) HDGGASR 587 Wild-type (AAV9.mRuby3) also used. euthanized month infusion. Scale bar fluorescence, whole turn images 200 μm. apex, upper middle, lower base 50 scale View Large Image Viewer Download Hi-res image

Language: Английский

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Investigation of inner ear drug delivery with a cochlear catheter in piglets as a representative model for human cochlear pharmacokinetics

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: March 9, 2023

Hearing impairment is the most common sensory disorder in humans, and yet hardly any medications are licensed for treatment of inner ear pathologies. Intricate pharmacokinetic examinations to better understand drug distribution within this complex organ could facilitate development novel therapeutics. For such translational research projects, animal models indispensable, but differences dimensions other anatomical features complicate transfer experimental results clinic. The gap between rodents humans may be bridged using larger as non-human primates. However, their use challenging impeded by administrative, regulatory, financial hurdles. Other large with more human-like scarce. In study, we analyzed ears piglets a potential representative model human established surgical approach intracochlear application subsequent apical sampling. Further, controlled delivery fluorescein isothiocyanate-dextran (FITC-d) was carried out after insertion novel, clinically applicable CE-marked cochlear catheter through round window membrane. Two, six, 24 hours single injection device, FITC-d determined sequential perilymph samples. fluorometrically assessed concentrations two were compared content control groups, which either had been injected simple needle puncture membrane or combination stapes vent hole. Our findings demonstrate not only significantly increased when also higher total all Additionally, concentration decreased six showed homogenous shorter observation times.

Language: Английский

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