AAV9 U7snRNA Gene Therapy to Treat Boys With DMD Exon 2 Duplications.

Phase I/IIa Systemic Gene Delivery Clinical Trial of scAAV9.U7.ACCA for Exon 2 Duplication-Associated Duchenne Muscular Dystrophy

Open-label, single dose clinical trial of scAAV9.U7.ACCA via peripheral limb vein injection for Duchenne muscular dystrophy boys who have a duplication of exon 2.

Study Overview

• Status: Completed
• Conditions: Duchenne Muscular Dystrophy
• Intervention / Treatment: Biological: scAAV9.U7.ACCA

Detailed Description

The proposed clinical trial is a systemic (intravenous) delivery of scAAV9.U7.ACCA for DMD patients with a duplication of exon 2 in the DMD gene. Preclinical data shows that the small nuclear RNA (snRNA) construct delivered by the scAAV9.U7.ACCA vector causes significant skipping of exon 2, resulting in exclusion of the exon from the mature messenger RNA (mRNA) with a high degree of efficiency, leading to mRNA containing only a single exon 2 (wild type [WT] mRNA) or no copies of exon 2 (Del2 mRNA). Translation of the wild-type mRNA results in entirely normal dystrophin protein, whereas translation of the Del2 mRNA via translational initiation of an internal ribosome entry sequence, or IRES) results in a highly functional isoform expressed in patients known to walk into their eighth decade.

The study is designed as an open-label trial to assess safety and obtain preliminary efficacy data. scAAV9.U7.ACCA will be delivered to the systemic circulation via peripheral limb vein.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 13 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than 6 months and less than 14 years
• Confirmed duplication of exon 2 in the DMD gene using a clinically accepted technique that completely defines the mutation
• Pre-ambulant (not yet walking) or ambulant (as defined by the ability to walk 10 meters without assistance)
• Males of any ethnic group will be eligible
• Ability to cooperate with muscle testing
• In subjects age 4 and above, stable dose and regimen of corticosteroid therapy (prednisone, deflazacort, or their generic forms) for at least 12 weeks prior to gene transfer.

Exclusion Criteria:

• Active viral infection based on clinical observations

• Symptoms or signs of cardiomyopathy, including:

  1. Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
  2. Echocardiogram with ejection fraction below 40%
• Serological evidence of HIV infection, or Hepatitis B or C infection
• Diagnosis of (or ongoing treatment for) an autoimmune disease
• Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the SI creates unnecessary risks for gene transfer
• AAV9 binding antibody titers ≥ 1:400 as determined by ELISA immunoassay
• Abnormal laboratory values in the clinically significant range as listed in Table 7, based upon normal values in the Nationwide Children's Hospital Laboratory.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (Minimal Efficacious Dose); The Minimal Effective Dose (MED) will be delivered.	Biological: scAAV9.U7.ACCA; A single dose of scAAV9.U7.ACCA will be systemically delivered via a peripheral vein injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Unacceptable Toxicity.	Unacceptable toxicity is defined as the occurrence of two or more unexpected Grade III or higher treatment-related toxicities, as defined by CTCAE 5.0.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Dystrophin Expression From Baseline Following Treatment With scAAV9.U7.ACCA.	Expression of dystrophin will be measured by immunofluorescent (IF) staining in muscle biopsies taken before and after gene therapy. This method allows for visualization of the protein and its proper location in the muscle fiber in comparison to normal protein expression.	1 year
Change in Dystrophin Expression From Baseline Following Treatment With scAAV9.U7.ACCA.	Expression of dystrophin will be quantified by western blotting in muscle biopsies taken before and after gene therapy. This method allows for quantification of the protein amount in comparison to normal protein expression amounts.	1 year
Changes in Percent of Exon 2 Skipping/Exclusion in the Dystrophin mRNA Transcript.	Exon 2 exclusion will be measured using RT-PCR analysis.	1 year

Collaborators and Investigators

• Sponsor: Megan Waldrop
• Collaborators: Astellas Pharma Inc; Audentes Therapeutics
• Investigators: Principal Investigator: Megan Waldrop, MD, Nationwide Children's Hospital

Publications and helpful links

General Publications

• Vulin A, Wein N, Simmons TR, Rutherford AM, Findlay AR, Yurkoski JA, Kaminoh Y, Flanigan KM. The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development. Neuromuscul Disord. 2015 Nov;25(11):827-34. doi: 10.1016/j.nmd.2015.08.005. Epub 2015 Aug 11.
• Gurvich OL, Maiti B, Weiss RB, Aggarwal G, Howard MT, Flanigan KM. DMD exon 1 truncating point mutations: amelioration of phenotype by alternative translation initiation in exon 6. Hum Mutat. 2009 Apr;30(4):633-40. doi: 10.1002/humu.20913.
• Flanigan KM, Dunn DM, von Niederhausern A, Howard MT, Mendell J, Connolly A, Saunders C, Modrcin A, Dasouki M, Comi GP, Del Bo R, Pickart A, Jacobson R, Finkel R, Medne L, Weiss RB. DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy. Neuromuscul Disord. 2009 Nov;19(11):743-8. doi: 10.1016/j.nmd.2009.08.010. Epub 2009 Sep 29.
• Vulin A, Barthelemy I, Goyenvalle A, Thibaud JL, Beley C, Griffith G, Benchaouir R, le Hir M, Unterfinger Y, Lorain S, Dreyfus P, Voit T, Carlier P, Blot S, Garcia L. Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping. Mol Ther. 2012 Nov;20(11):2120-33. doi: 10.1038/mt.2012.181. Epub 2012 Sep 11.
• Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlen M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Brioschi S, Bovolenta M, Neri M, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM. Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 2014 Sep;20(9):992-1000. doi: 10.1038/nm.3628. Epub 2014 Aug 10.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2020
• Primary Completion (Actual): November 13, 2023
• Study Completion (Actual): July 1, 2025

Study Registration Dates

• First Submitted: January 22, 2020
• First Submitted That Met QC Criteria: January 22, 2020
• First Posted (Actual): January 27, 2020

Study Record Updates

• Last Update Posted (Estimated): September 11, 2025
• Last Update Submitted That Met QC Criteria: August 21, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Muscular Disorders, Atrophic; Muscular Dystrophies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Muscular Dystrophy, Duchenne
• Other Study ID Numbers: AAV9 Dup2 U7

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No