Duchenne Muscular Dystrophy
Conditions
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.
Interventions
BIOLOGICALscAAV9.U7.ACCA
A single dose of scAAV9.U7.ACCA will be systemically delivered via a peripheral vein injection.
Sponsors
Audentes Therapeutics
Astellas Pharma Inc
Megan Waldrop
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
MALE
Age
6 Months to 13 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Unacceptable Toxicity. | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Dystrophin Expression From Baseline Following Treatment With scAAV9.U7.ACCA. | 1 year | 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. |
| Changes in Percent of Exon 2 Skipping/Exclusion in the Dystrophin mRNA Transcript. | 1 year | Exon 2 exclusion will be measured using RT-PCR analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Minimal Efficacious Dose) The Minimal Effective Dose (MED) will be delivered.
scAAV9.U7.ACCA: A single dose of scAAV9.U7.ACCA will be systemically delivered via a peripheral vein injection. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Cohort 1 (Minimal Efficacious Dose) |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 8 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
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.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Number of Participants With Unacceptable Toxicity. | 0 Participants |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Change in Dystrophin Expression From Baseline Following Treatment With scAAV9.U7.ACCA. | 46.6 % Change in dystrophin expression | Standard Deviation 36.8 |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Change in Dystrophin Expression From Baseline Following Treatment With scAAV9.U7.ACCA. | 30.1 % Change in dystrophin expression | Standard Deviation 38.6 |
Secondary
Changes in Percent of Exon 2 Skipping/Exclusion in the Dystrophin mRNA Transcript.
Exon 2 exclusion will be measured using RT-PCR analysis.
Time frame: 1 year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Minimal Efficacious Dose) | Changes in Percent of Exon 2 Skipping/Exclusion in the Dystrophin mRNA Transcript. | Skipping of 1 Exon 2 | 4.9 % Exon 2 Exclusion | Standard Deviation 4.8 |
| Cohort 1 (Minimal Efficacious Dose) | Changes in Percent of Exon 2 Skipping/Exclusion in the Dystrophin mRNA Transcript. | Skipping of 2 Exons 2 | 33.6 % Exon 2 Exclusion | Standard Deviation 45.4 |