In vivoselection in non-human primates identifies superior AAV capsids for on-target CSF delivery to spinal cord DOI Creative Commons
Killian S. Hanlon, Ming Cheng,

Demitri de la Cruz

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 13, 2023

Abstract Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal delivery AAV into the cerebral fluid (CSF) can avoid many issues systemic delivery, although achieving broad distribution vector transgene expression throughout is challenging entry to periphery occurs, sometimes initiating hepatotoxicity. Here we performed two rounds in vivo biopanning non-human primates (NHPs) with an AAV9 peptide display library injected intrathecally insert sequencing on DNA isolated from either whole tissue (conventional selection), nuclei, or nuclei transgene-expressing cells. A subsequent barcoded pool candidates was compared (biodistribution) RNA (expression) level liver NHPs. Most displayed enhanced biodistribution all levels ranging 2 265-fold. Nuclear isolation expression-based selection yielded 4 7 candidate capsids (up 2.4-fold), while no capsid obtained by conventional achieved level. Furthermore, several lower up 1,250-fold, AAV9, providing a remarkable target/off target ratio. These may have potential programs directed method described here should be useful clinically relevant large animal models.

Language: Английский

Drug delivery systems for CRISPR-based genome editors DOI
Victoria J. Madigan, Feng Zhang, James E. Dahlman

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(11), P. 875 - 894

Published: Sept. 18, 2023

Language: Английский

Citations

76
Therapeutic approaches for Duchenne muscular dystrophy DOI
Thomas C. Roberts, Matthew J. A. Wood, Kay E. Davies

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(11), P. 917 - 934

Published: Aug. 31, 2023

Language: Английский

Citations

60
Chemically Modified Platforms for Better RNA Therapeutics DOI

Yesi Shi,

Xueyan Zhen,

Yiming Zhang

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(3), P. 929 - 1033

Published: Jan. 29, 2024

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential disease prevention and treatment. However, despite their remarkable achievements, these encounter substantial challenges including low stability, susceptibility to degradation by nucleases, prominent negative charge, thereby hindering further development. Chemically modified platforms emerged as strategic innovation, focusing on precise alterations either RNA moieties or associated delivery vectors. This comprehensive review delves into platforms, underscoring significance augmenting performance translational prospects of therapeutics. It encompasses an in-depth analysis various chemically that been instrumental propelling therapeutics toward clinical utility. Moreover, scrutinizes rationale behind diverse chemical modification techniques aiming at optimizing therapeutic efficacy molecules, facilitating robust management. Recent empirical studies corroborating enhancement through modifications are highlighted. Conclusively, we offer profound insights transformative impact drugs delineates prospective trajectories for future development integration.

Language: Английский

Citations

51
Global seroprevalence of neutralizing antibodies against adeno-associated virus serotypes used for human gene therapies DOI Creative Commons
Amit Chhabra,

George Bashirians,

Christos J. Petropoulos

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2024, Volume and Issue: 32(3), P. 101273 - 101273

Published: May 29, 2024

Adeno-associated virus (AAV) vectors are promising gene therapy candidates, but pre-existing anti-AAV neutralizing antibodies (NAbs) pose a significant challenge to successful delivery. Knowledge of NAb seroprevalence remains limited and inconsistent. We measured activity NAbs against six clinically relevant AAV serotypes across 10 countries in adults (

Language: Английский

Citations

13
Management of Select Adverse Events Following Delandistrogene Moxeparvovec Gene Therapy for Patients With Duchenne Muscular Dystrophy DOI Creative Commons
Craig M. Zaidman, Natalie L. Goedeker,

Amal Aqul

et al.

Journal of Neuromuscular Diseases, Journal Year: 2024, Volume and Issue: 11(3), P. 687 - 699

Published: April 12, 2024

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to absence of functional protein. Individuals living with DMD exhibit progressive muscle weakness resulting loss ambulation and limb function, respiratory insufficiency, cardiomyopathy, multiorgan involvement. Adeno-associated virus vector-mediated therapy designed enable production protein new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) indicated for treatment ambulatory pediatric patients aged 4 through 5 years who have an mutation gene. OBJECTIVE: Evidence-based considerations management potential adverse events following are lacking clinical literature. Our goal was provide interdisciplinary consensus selected treatment-related (TRAEs) (vomiting, acute liver injury, myocarditis, immune-mediated myositis) that may arise dosing delandistrogene moxeparvovec. METHODS: An panel 12 specialists utilized modified Delphi process develop evaluation TRAEs reported studies. Panelists completed 2 Questionnaires prior gathering in-person discussion. Consensus defined as majority (≥58% ; 7/12) panelists either agreeing or disagreeing. RESULTS: agreed choice baseline assessments should be informed by individual indications, treating provider’s judgment, prescribing information. Corticosteroid optimized considering risk versus benefit each indication. In all cases involving confirmed TRAE, consultations appropriate were suggested. CONCLUSIONS: The Panel established receiving moxeparvovec, including vomiting, myositis.

Language: Английский

Citations

7
Understanding and Tackling Immune Responses to Adeno-Associated Viral Vectors DOI
Helena Costa Verdera, Carmen Unzu, Erika Valeri

et al.

Human Gene Therapy, Journal Year: 2023, Volume and Issue: 34(17-18), P. 836 - 852

Published: Sept. 1, 2023

As the clinical experience in adeno-associated viral (AAV) vector-based gene therapies is expanding, necessity to better understand and control host immune responses also increasing. Immunogenicity of AAV vectors humans has been linked several limitations platform, including lack efficacy due antibody-mediated neutralization, tissue inflammation, loss transgene expression, some cases, complement activation acute toxicities. Nevertheless, significant knowledge gaps remain our understanding mechanisms therapies, further hampered by failure preclinical animal models recapitulate findings. In this review, we focus on current regarding responses, spanning from innate immunity humoral adaptive triggered how they can be mitigated for safer, durable, more effective therapies.

Language: Английский

Citations

14
Building CRISPR Gene Therapies for the Central Nervous System DOI
Sally Salomonsson, Claire D. Clelland

JAMA Neurology, Journal Year: 2024, Volume and Issue: 81(3), P. 283 - 283

Published: Jan. 29, 2024

Gene editing using clustered regularly interspaced short palindromic repeats (CRISPR) holds the promise to arrest or cure monogenic disease if it can be determined which genetic change create without inducing unintended cellular dysfunction and how deliver this technology target organ reliably safely. Clinical trials for blood liver disorders, delivery of CRISPR is not limiting, show promise, yet no have begun central nervous system (CNS) indications.

Language: Английский

Citations

6
Non-viral delivery of nucleic acid for treatment of rare diseases of the muscle DOI

Divya Rao,

Munia Ganguli

Journal of Biosciences, Journal Year: 2024, Volume and Issue: 49(1)

Published: Feb. 16, 2024

Language: Английский

Citations

6
The complex landscape of DMD mutations: moving towards personalized medicine DOI Creative Commons
Francesca Gatto, Silvia Benemei, Giulio Piluso

et al.

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: March 26, 2024

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused mutations in the DMD gene, encoding protein dystrophin. Various result different phenotypes disease severity. Understanding genotype/phenotype correlations essential to optimize clinical care, as mutation-specific therapies innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing severity phenotypic expressivity, may modulate response therapy, become new targets. Uncovering more genes via extensive genomic mapping studies offers potential fine-tune prognostic assessments for individuals DMD. This review provides insights into influence of

Language: Английский

Citations

5
Evolving Therapeutic Options for the Treatment of Duchenne Muscular Dystrophy DOI Creative Commons
Eleonora S. D’Ambrosio, Jerry R. Mendell

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(6), P. 1669 - 1681

Published: Sept. 6, 2023

Language: Английский

Citations

11