AT702 / Astellas - LARVOL DELTA

New In Vitro Models System for Treat Pitt Hopkins Syndrome (ASGCT 2024) - "Moreover, using mouse embryonic fibroblasts expressing GFP under the control of the human TCF4 promoter, we showed upregulation of GFP expression following AAV9.U7-TCF4 treatment as well in yet another model system... We developed a novel U7 small RNA based technology allowing modulating TCF4 promoter activity. Our data indicates efficacy of the approach in HEK293 cells as well as multiple reprogrammed patient cell lines and mouse embryonic fibroblasts expressing GFP under the human TCF4 promoter. Our novel therapeutic strategy is highly promising and could be advantageous over existing gene replacement strategies as it would allow to use the endogenous gene to generate all naturally occurring TCF4 isoforms instead of delivery a single transcript."

Preclinical • Developmental Disorders • Gene Therapies • Mental Retardation • TCF4

Persistence of exon 2 skipping and dystrophin expression at 18 months after U7snRNA-mediated therapy in the Dup2 mouse model. (PubMed, Mol Ther Methods Clin Dev) - "Significant exon 2 skipping and robust dystrophin expression in the muscles and hearts of treated mice persist at 18 months after treatment, along with the partial rescue of muscle function. These data extend our previous findings and show that scAAV9.U7.ACCA provides long-term protection by restoring the disrupted dystrophin reading frame in the context of exon 2 duplications."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Sustained Dystrophin Expression in an Infant with a DMD Exon 2 Duplication Following Dosing with scAAV9.U7-ACCA (ASGCT 2023) - "Dystrophin protein expression was similarly robust and sustained, with immunofluorescence showing ~95% dystrophin positive fibers and western blot showing levels of 88.3% of normal (increased from 70.1% at the month 4 biopsy). We conclude that treatment with scAA9.U7-ACCA in infancy is safe and robustly efficacious with therapeutic effect sustained over at least 12 months, supporting continued clinical investigation."

Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy. (PubMed, Pharmaceutics) - "These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown."

Journal • Review • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Automated Immunofluorescence Analysis of Dystrophin and Other Markers in Mouse Muscle and Heart Sections (ASGCT 2022) - "After systemically treating Dup2 mice with our AAV9.U7.ACCA vector to induce U7snRNA-mediated skipping of exon 2, we show widespread restoration of dystrophin signal at the sarcolemma throughout whole sections from multiple muscles and the heart, accompanied by reduction in central nucleation in treated muscles...We have published previous work validating that this methodology also shows good repeatability and reproducibility between different operators in human dystrophinopathy biopsies showing a wide range of dystrophin expression levels. We anticipate that making this analysis approach available to more investigators will significantly contribute to progress in preclinical research aiming to develop gene therapies for DMD."

Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Safety and Outcomes of Intravenous scAAV9.U7-ACCA for the Treatment of Duchenne Muscular Dystrophy Caused by Exon 2 Duplications (ASGCT 2022) - "Muscle biopsy of the first two subjects through 12 and 6 months respectively shows expression of apparent full-length dystrophin protein, quantified by Western blot at levels of ~6% in the younger (9.0 years) subject and BLOQ/~1-2% in the older (13.7 years) subject, possibly reflecting differences in myofiber transfection due to differing degrees of dystrophic skeletal muscle changes. These findings represent the continued therapeutic expression of apparent full-length dystrophin in subject 1, continued safety through up to 18 months post gene transfer, and the first evidence of safety for early systemic viral vector delivery in an infant with DMD."

Clinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

AAV9 U7snRNA Gene Therapy to Treat Boys With DMD Exon 2 Duplications. (clinicaltrials.gov) - P1/2; N=3; Active, not recruiting; Sponsor: Megan Waldrop; Enrolling by invitation ➔ Active, not recruiting; Trial completion date: Jan 2025 ➔ Nov 2025; Trial primary completion date: Jan 2023 ➔ Nov 2023

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Absence of significant off-target splicing variation with a U7snRNA vector targeting DMD exon 2 duplications. (PubMed, Hum Gene Ther) - "We have developed an AAV vector (AAV9.U7-ACCA) containing four U7snRNAs targeting the splice donor and acceptor sites of dystrophin exon 2, resulting in highly efficient exclusion of DMD exon 2...In contrast, four LSVs represented significant on-target correction of Dmd exon 2 splicing and transcriptome analysis showed correction of known dystrophin-deficient gene dysregulation. We conclude that the absence of off-target splicing induced by treatment with the U7-ACCA vector supports the continued clinical development of this approach."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Gene Therapy for Duchenne Muscular Dystrophy Due to Duplications of Exon 2 Using the scAAV9.U7-ACCA Vector: 6-12 Months Clinical Follow Up (ASGCT 2021) - P1/2 | "Additionally, at 12 months for subject 1 improvements in the 100 meter timed test (61.4% predicted), NSAA (27), and 4 stair climb (2.39 sec) were seen. These findings represent the first therapeutic expression of apparent full-length dystrophin in a human gene therapy trial, continued safety at up to 12 months post gene transfer, and support continued clinical investigation."

Clinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] The Long-Term Efficiency of the scAAV.U7.ACCA Vector in Inducing Dystrophin Expression in Adult Dup2 Mice (ASGCT 2021) - P1/2 | "The single scAAV9.U7.ACCA injection resulted in a dramatic improvement in specific force output, which increased up to 64-76% in Dia and TA muscles, respectively, and better protection of the TA muscle from repeated fatigue, which improved up to 73%. Overall, these data support our previous findings showing that scAAV9.U7.ACCA provides long-term protection by restoring the disrupted dystrophin reading frame in straight muscles from Dup2 mice and functional recovery of TA and Dia muscles 18-month post vector administration."

Preclinical • Duchenne Muscular Dystrophy • Fatigue • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Expression of apparent full-length dystrophin in skeletal muscle in a first-in-human gene therapy trial using the scAAV9.U7-ACCA vector (MDA 2021) - P1/2 | "Functional outcome measures remained stable or improved. These findings represent the first therapeutic expression of apparent full-length dystrophin in a human gene therapy trial and support continued clinical investigation."

P1 data • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Absence of Toxicity with Intravenous Dosing of the Exon 2-Skipping AAV9.U7-ACCA Vector in Non-Human Primates (MDA 2021) - "Here we present the data from a rigorous dose-escalation toxicity study in nonhuman primates, encompassing two doses (3E13 vg/kg and 8E13 vg/kg) and two time points (3- and 6- months post-injection). No evidence for significant toxicity was seen by biochemical, histopathologic, or clinical measures, providing evidence for safety that led to initiation of a first-in-human clinical trial."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Lack of toxicity in non-human primates receiving clinically relevant doses of an AAV9.U7snRNA vector designed to induce DMD exon 2 skipping. (PubMed, Hum Gene Ther) - "Here we present the data from a rigorous dose-escalation toxicity study in nonhuman primates, encompassing two doses (3 x 1013 vg/kg and 8 x 1013 vg/kg) and two time points (3- and 6- months post-injection). No evidence for significant toxicity was seen by biochemical, histopathologic, or clinical measures, providing evidence for safety that led to initiation of a first-in-human clinical trial."

Clinical • Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

[VIRTUAL] Expression of apparent full-length dystrophin in skeletal muscle in a first-in-human gene therapy trial using the scAAV9.U7-ACCA vector (WMS 2020) - No abstract available

Late-breaking abstract • P1 data • Gene Therapies

[VIRTUAL] Absence of toxicity with intravenous dosing of the Exon 2-skipping AAV9.U7-ACCA vector in non-human primates (WMS 2020) - No abstract available

Long-Term Efficacy of AAV9-U7snRNA-Mediated Exon 51 Skipping in mdx52 Mice. (PubMed, Mol Ther Methods Clin Dev) - "In this study, we examined the therapeutic potential of an AAV-U7snRNA targeting the human DMD exon 51, which could be applicable to 13% of DMD patients. A single injection of AAV9-U7 exon 51 (U7ex51) induces widespread and sustained levels of exon 51 skipping, leading to significant restoration of dystrophin and improvement of the dystrophic phenotype in the mdx52 mouse...Additionally, while low levels of exon skipping were measured in the brain, the dystrophin protein could not be detected, in line with a lack of improvement of their abnormal behavioral fear response. These results thus confirm the high therapeutic potential of the AAV-mediated exon-skipping approach, yet the apparent discrepancies between exon skipping and protein restoration levels suggest some limitations of this experimental model."

Journal • Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Audentes Therapeutics reports third quarter 2019 financial results and provides corporate update (Businesswire) - "AT702/AT753/AT751 for Duchenne Muscular Dystrophy (DMD)...IND-enabling dose ranging and toxicology studies underway for AT702; on-track for first quarter 2020 IND submission and plan to initiate a clinical study in the second quarter of 2020....AT753 exon 53 targeting oligonucleotide sequence selected; manufacturing underway to support IND-enabling preclinical studies to be initiated this quarter....AT751 exon 51 targeting oligonucleotide screening underway; plan to initiate IND-enabling preclinical studies in the first quarter of 2020."

IND • New trial • Preclinical