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

Megan Waldrop

Status and phase

Active, not recruiting

Phase 2

Phase 1

Conditions

Duchenne Muscular Dystrophy

Treatments

Biological: scAAV9.U7.ACCA

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT04240314

AAV9 Dup2 U7

Details and patient eligibility

About

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.

Full 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.

Enrollment

3 patients

Sex

Male

Ages

6 months to 13 years old

Volunteers

No Healthy Volunteers

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.