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

Study Overview
=================
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.

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

Conditions
-----------------
Duchenne Muscular Dystrophy

Intervention / Treatment
-----------------
* Biological: scAAV9.U7.ACCA


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 13 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 staining in muscle biopsies taken before and after gene therapy. | 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. | 1 year | 
| Changes in exon 2 inclusion in the dystrophin mRNA transcript. | Exon 2 inclusion will be measured using RT-PCR analysis. | 1 year |