start date: January 4, 2018
estimated completion: April 2021
phase of development:
Phase 1/Phase 2
size / enrollment: 4
study description:
In the study, the gene will be infused via peripheral arm vein so that it can reach all the muscles in the body. Six DMD subjects ages 3 months to 3 years in Cohort A, and six DMD subjects ages 4 years to age 7 years in Cohort B, will be enrolled. All subjects will receive intravenous micro-dystrophin vector (2X10e14 vg/kg in 10mL/kg). Subjects will have infusions over 1 hour in the Pediatric Intensive Care Unit (PICU) at Nationwide Children's Hospital. Before the gene therapy a muscle biopsy will be done at the screening visit. Subjects will have a second muscle biopsy to see if the gene allowed for replacement of the missing dystrophin protein at 90 days post delivery. After the gene transfer, patients will be carefully monitored for any side effects of the treatment. This will include blood and urine tests, as well as physical examination during the screening visits and on days 0, 1, 7, 14, 30, 60, 90, and 180, and at months 9, 12, 18, 24, 30 and 36 to make sure that there are no side effects from the gene injection.
primary outcomes:
- Safety based on number of participants with adverse events. [Time Frame: 3 years]
AEs will be monitored and scored for severity and relatedness to the study article.
secondary outcomes:
- Gross Motor Subtest Scaled (Bayley-III) score [Time Frame: Screening, Day 30-3 Years]
Gross Motor Scaled Score measures motor development. The Bayley-III Gross Motor Subtest will be scored for Cohort A on every follow up visit starting at Day 30 through 3 years. Any subject that is 43-47 months of age, inclusive, at time of screening will have the scaled score calculated compared to normative data for 42 month old children. The Bayley-III provides normative data for children 1-42 months of age.
- Physical Therapy Assessments The 100 Meter Timed Test (100m) [Time Frame: Screening, Day 30-3 Years]
The 100m will be the primary motor outcome for Cohort B. The 100 Meter Timed Test will be an exploratory outcome initiated for Cohort A as soon as the child is 3 years of age.
- Physical Therapy Assessments North Star Ambulatory Assessment (NSAA) [Time Frame: Screening, Day 30-3 Years]
The North Star Ambulatory Assessment (NSAA) will be an exploratory outcome initiated for Cohort A as soon as the child is four years of age and for cohort B. The NSAA measures the quality of ambulation in young boys with Duchenne Muscular Dystrophy.
- Physical Therapy Assessments Timed Up and Go modified for children (TUG) [Time Frame: Screening, Day 30-3 Years]
Exploratory outcomes for Cohort B will include the Timed Up and Go modified for children (TUG).
- Physical Therapy Assessments Ascend and Descend of 4 steps [Time Frame: Screening, Day 30-3 Years
Exploratory outcomes for Cohort B will include ascend and descend of 4 steps.
- Physical Therapy Assessments Hand Held Dynamometry (HHD) [Time Frame: Screening, Day 30-3 Years]
Exploratory outcomes for Cohort B will include and hand held dynamometry (HHD) for knee extensors and knee flexors, and elbow flexors and elbow extensors.
- Micro-dystrophin gene expression quantification by immunofluorescence [Time Frame: Screening and Day 90]
Micro-dystrophin gene expression levels will be quantified by immunofluorescence and compared in pre and post muscle biopsies.
- Micro-dystrophin gene expression quantification by western blot [Time Frame: Screening and Day 90]
Micro-dystrophin gene expression levels will be quantified by western blot analysis and compared in pre and post muscle biopsies.
- A decrease in CK following gene therapy [Time Frame: 3 years]
Decrease in CK levels in circulating blood
inclusion criteria:
• Cohort A subjects: 3 months to 3 years of age, inclusive
• Cohort B subjects: 4 to 7 years of age, inclusive
• Molecular characterization of the DMD gene with frameshift (deletion or duplication), or premature stop codon mutation between exons 18 to 58
• CK elevation >1000 U/L
• Cohort A subjects: below average on the Bayley-III motor assessment for gross motor defined as a scaled score of <=9.
• Cohort B subjects: below average on the 100 Meter Timed Test defined as <=80% predicted.
• Males of any ethnic group
• Ability to cooperate with motor assessment testing.
• Cohort A subjects: No previous treatment with corticosteroids.
• Cohort B subjects: Stable dose equivalent of oral corticosteroids for at least 12 weeks prior to screening and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study.
exclusion criteria:
• Active viral infection based on clinical observations.
• Signs of cardiomyopathy, including 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.
• Abnormal laboratory values considered clinically significant.
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer.
• Subjects with AAVrh74 or AAV8 antibody titers > 1:400 as determined by ELISA immunoassay.
• Medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability.
• Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed).
• Received any investigational medication (other than corticosteroids) or exon skipping medications (including ExonDys 51), experimental or otherwise, in the last 6 months prior to screening for this study.
• Received any type of gene therapy, cell based therapy (e.g. stem cell transplantation), or CRISPR/Cas9.
• Family does not want to disclose patient's study participation with primary care physician and other medical providers.
