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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04240314
Recruitment Status : Active, not recruiting
First Posted : January 27, 2020
Last Update Posted : December 9, 2021
Audentes Therapeutics
Information provided by (Responsible Party):
Megan Waldrop, Nationwide Children's Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Biological: scAAV9.U7.ACCA Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This trial will deliver the minimal efficacious dose as determined by preclinical studies and approved by the FDA to determine safety and target engagement.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/IIa Systemic Gene Delivery Clinical Trial of scAAV9.U7.ACCA for Exon 2 Duplication-Associated Duchenne Muscular Dystrophy
Actual Study Start Date : January 15, 2020
Estimated Primary Completion Date : November 19, 2023
Estimated Study Completion Date : November 19, 2025

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.

Primary Outcome Measures :
  1. Monitoring for the development of unacceptable toxicity. [ Time Frame: 2 years ]
    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.

Secondary Outcome Measures :
  1. Change in dystrophin expression from baseline following treatment with scAAV9.U7.ACCA. [ Time Frame: 1 year ]
    Expression of dystrophin will be measured by immunofluorescent staining in muscle biopsies taken before and after gene therapy.

  2. Change in dystrophin expression from baseline following treatment with scAAV9.U7.ACCA. [ Time Frame: 1 year ]
    Expression of dystrophin will be quantified by western blotting in muscle biopsies taken before and after gene therapy.

  3. Changes in exon 2 inclusion in the dystrophin mRNA transcript. [ Time Frame: 1 year ]
    Exon 2 inclusion will be measured using RT-PCR analysis.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   6 Months to 13 Years   (Child)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04240314

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United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Sponsors and Collaborators
Megan Waldrop
Audentes Therapeutics
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Principal Investigator: Megan Waldrop, MD Nationwide Children's Hospital

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Responsible Party: Megan Waldrop, Professor of Neurology, Nationwide Children's Hospital Identifier: NCT04240314    
Other Study ID Numbers: AAV9 Dup2 U7
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: December 9, 2021
Last Verified: November 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked