AAV9 U7snRNA Gene Therapy to Treat Boys With DMD Exon 2 Duplications.
Primary Purpose
Duchenne Muscular Dystrophy
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
scAAV9.U7.ACCA
Sponsored by
About this trial
This is an interventional treatment trial for Duchenne Muscular Dystrophy
Eligibility Criteria
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:
- Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
- 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.
Sites / Locations
- Nationwide Children's Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Cohort 1 (Minimal Efficacious Dose)
Arm Description
The Minimal Effective Dose (MED) will be delivered.
Outcomes
Primary Outcome Measures
Monitoring for the development of 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.
Secondary Outcome Measures
Change in dystrophin expression from baseline following treatment with scAAV9.U7.ACCA.
Expression of dystrophin will be measured by immunofluorescent staining in muscle biopsies taken before and after gene therapy.
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.
Changes in exon 2 inclusion in the dystrophin mRNA transcript.
Exon 2 inclusion will be measured using RT-PCR analysis.
Full Information
NCT ID
NCT04240314
First Posted
January 22, 2020
Last Updated
February 7, 2023
Sponsor
Megan Waldrop
Collaborators
Audentes Therapeutics
1. Study Identification
Unique Protocol Identification Number
NCT04240314
Brief Title
AAV9 U7snRNA Gene Therapy to Treat Boys With DMD Exon 2 Duplications.
Official Title
Phase I/IIa Systemic Gene Delivery Clinical Trial of scAAV9.U7.ACCA for Exon 2 Duplication-Associated Duchenne Muscular Dystrophy
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 15, 2020 (Actual)
Primary Completion Date
November 19, 2023 (Anticipated)
Study Completion Date
November 19, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Megan Waldrop
Collaborators
Audentes Therapeutics
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Duchenne Muscular Dystrophy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1 (Minimal Efficacious Dose)
Arm Type
Experimental
Arm Description
The Minimal Effective Dose (MED) will be delivered.
Intervention Type
Biological
Intervention Name(s)
scAAV9.U7.ACCA
Intervention Description
A single dose of scAAV9.U7.ACCA will be systemically delivered via a peripheral vein injection.
Primary Outcome Measure Information:
Title
Monitoring for the development of unacceptable toxicity.
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Change in dystrophin expression from baseline following treatment with scAAV9.U7.ACCA.
Description
Expression of dystrophin will be measured by immunofluorescent staining in muscle biopsies taken before and after gene therapy.
Time Frame
1 year
Title
Change in dystrophin expression from baseline following treatment with scAAV9.U7.ACCA.
Description
Expression of dystrophin will be quantified by western blotting in muscle biopsies taken before and after gene therapy.
Time Frame
1 year
Title
Changes in exon 2 inclusion in the dystrophin mRNA transcript.
Description
Exon 2 inclusion will be measured using RT-PCR analysis.
Time Frame
1 year
10. Eligibility
Sex
Male
Gender Based
Yes
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Megan Waldrop, MD
Organizational Affiliation
Nationwide Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
25108525
Citation
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. Erratum In: Nat Med. 2015 Apr;21(4):414. Nat Med. 2015 May;21(5):537. Brioschi, Simona [added]; Bovolenta, Matteo [added]; Neri, Marcella [added].
Results Reference
background
PubMed Identifier
26365037
Citation
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.
Results Reference
background
PubMed Identifier
19206170
Citation
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.
Results Reference
background
PubMed Identifier
19793655
Citation
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.
Results Reference
background
PubMed Identifier
22968479
Citation
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.
Results Reference
background
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AAV9 U7snRNA Gene Therapy to Treat Boys With DMD Exon 2 Duplications.
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