Duchenne Muscular Dystrophy (DMD)
Conditions
Keywords
Duchenne Muscular Dystrophy, DMD, Gene therapy, Gene editing, Muscular dystrophies, Hereditary neuromuscular disorders
Brief summary
The study will evaluate the safety and tolerability of GEN6050X gene therapy in Duchenne muscular dystrophy (DMD) patients amenable to exon 50 skipping.
Detailed description
GEN6050X is an intravenously administered human DMD exon 50 skipping base editing drug containing dual single-stranded adeno-associated virus serotype 9 (ss.AAV9) vectors. The study is a first-in-human, single-arm, open-label, single-center clinical trial to evaluate safety and tolerability of a single intravenous infusion of GEN6050X in ambulatory boys with DMD. Other objectives include pharmacokinetics, pharmacodynamics, and the preliminary clinical efficacy of GEN6050X over 52 weeks. A total of three ambulatory pediatric participants (aged 4 to 9 years old) are expected to enroll, each receiving a dose of 5×10\^13 vg/kg. These participants will be dosed in a staggered fashion. Safety assessments will include monitoring of adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations throughout the study duration. In addition, a comprehensive short-term prophylactic immunosuppression regimen(including rituximab and sirolimus) will be administered prior to treatment in order to mitigate potential immune response.
Interventions
GENETICGEN6050X intravenous injection
GEN6050X is an intravenously administered human DMD exon 50 skipping base editing drug.
Sponsors
Peking Union Medical College Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single-arm unblinded, single-center study
Eligibility
Sex/Gender
MALE
Age
4 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
1. Subject age: 4-10 years old (including 10 years old) 2. Gender: Male 3. Patients with DMD gene exon deletion types confirmed by molecular diagnosis: 8-49, 20-49, 22-49, 51, 51-53, 51-55, 51-57, 51-59, 51-60, 51-67, 51-69, 51-75 or 51-78 and other mutations amenable to exon 50 skipping. 4. The participant is able to walk independently and completes the 10-meter walk test without assistance. 5. Participant is able to complete time to stand from supine independently in less than 30s. 6. The participant is able to cooperate with motor assessment testing. 7. Receipt of glucocorticoids for 6 months and a stable daily dose for at least 12 weeks prior to study entry 8. Ability to tolerate muscle biopsies under anesthesia with no contraindications to these procedures.
Exclusion criteria
1. Participants are in the active period of viral infection, including infections such as TORCH virus, Epstein-Barr(EB) virus, and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). 2. Received a live attenuated vaccine within 3 months prior to receiving GEN6050X, or was exposed to an influenza (or other inactivated) vaccine within 30 days prior to receiving GEN6050X, or received systemic antiviral, anti-infective, and/or interferon therapy. 3. Serological tests found HIV, Hepatitis B Virus(HBV), hepatitis C virus(HCV), and syphilis infection. 4. Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks prior to receiving gene therapy. 5. With clear symptoms of cardiomyopathy, echocardiography shows that the left ventricular ejection fraction is less than 40%. 6. Need for continuous or intermittent assisted support from a ventilator. 7. Diagnosed with autoimmune disease or receiving related treatment for autoimmune disease. 8. The following indicators are abnormal in laboratory biochemical testing: γ-glutamyl transpeptidase (GGT) above the 2-fold upper limit and total bilirubin above 1.5 times the upper limit, cystatin C (cystatin C) \> 1.27 mg/L, hemoglobin (Hgb) \< 100 or \>200 g/L; Leukocytes (WBC) \> 18.5×10\^9/L or platelet ≤ 125×10\^9/L. 9. The titer of AAV9 neutralizing antibody determined by cell suppression assay \> 1:50. 10. Patients have received any gene therapy (e.g., adeno associated virus(AAV) gene therapy), cell therapy (e.g., stem cell transplantation), in vivo editing, or ex vivo editing therapy (e.g., CRISPR-Cas9, TALEN) in the past. 11. Participant has any contraindication to immunosuppressive therapy. 12. Has a medical condition or extenuating circumstance that, in the opinion of the principal investigator, is unsuitable for participation in the clinical trial. 13. The family does not wish to disclose the patient's study participation to the attending physician and other medical providers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of GEN6050X measured by incidence of adverse events (AEs). | through 1 year post-treatment | Incidence of dose-limiting safety or intolerability, as measured by treatment-related adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) V5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Physical Therapy Assessment Time to run/walk 10 meters(TTRW) | Screening, 6 months-3 Years | Change in Time to Run/Walk 10 Meters Test (TTRW) |
| Physical Therapy Assessment 6MWT | Screening, 6 months-3 Years | Change in Six-minutes Walk Test (6MWT) |
| Physical Therapy Assessments Change in Time to Stand (TTSTAND) | Screening, 6 months-3 Years | Change in Time to Stand (TTSTAND) |
| Physical Therapy Assessments Ascend and Descend of 4 steps | Screening, 6 months-3 Years | Change in Time to Climb 4 Steps Test |
| Physical Therapy Assessment North Star Ambulatory Assessment (NSAA） | Screening, 6 months-3 Years | The NSAA measures the quality of ambulation in young boys with Duchenne Muscular Dystrophy. |
| Physical Therapy Assessments upper limb function | Screening, 6 months-3 Years | Change score in Performance of Upper Limb (PUL) 2.0 |
| Physical Therapy Assessments Pulmonary function | Screening, 6 months-3 Years | Change in pulmonary function test |
| Dystrophin protein expression | 24 weeks post-treatment | Dystrophin protein recovery level in muscle biopsy. |
| Serum creatine kinase(CK) | through 1 year post-treatment | Decrease in CK levels in circulating blood |
| Physical Therapy Assessments Hand-held dynamometer | Screening, 6 months-3 Years | The force generated for each muscle strength (elbow extension, elbow flexion, knee extension, and knee flexion on the dominant side only) will be measured by Hand-held dynamometer. |
Countries
China
Outcome results
None listed