Safety and Dystrophin Expression of SPOT-mRNA03 in Duchenne Muscular Dystrophy (DMD) Patients

Shanghai Siponuoyin Biotechnology Co Ltd

Status and phase: Enrolling; Early Phase 1

Conditions: Duchenne Muscular Dystrophy (DMD)

Treatments: Genetic: mRNA

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT07188012

FM-T3-SH

Details and patient eligibility

About

The primary objective of this study is to evaluate the safety and and tolerability of SPOT-mRNA03 administered by intravenous (IV) infusion to DMD patients. In addition, this study will preliminarily investigate the concentration changes in dystrophin mRNA concentration, dystrophin protein expression and engraftment, as well as cytokine profiles and immunogenicity.

Full description

This is a FIH, open-label, single-arm, and single-center exploratory clinical study of SPOT-mRNA03 administered via IV infusion for DMD patients. SPOT-mRNA03 is a muscle-targeted extracellular vesicles (EVs) loaded with full-length dystrophin mRNA. The targeting ability of SPOT-mRNA03 is conferred by molecular targeting peptides on the EVs membrane, enabling the delivery of dystrophin mRNA as a gene therapy product for DMD.

The study has two ascending dose cohorts, 5.0 × 10^9 CN dystrophin mRNA / kg and 5.0 × 10^10 CN dystrophin mRNA / kg. The study will have a screening period of 30 days, during which patients or their legal guardian written informed consent will be obtained before screening assessments and eligibility will be determined. A total of 6 eligible subjects will participate in the study with 3 subjects in each dose cohort [No previous treatment with corticosteroids]. All subjects started taking 0.05-0.1mg/kg (adjusted according to the actual clinical situation) tacrolimus or sirolimus orally once daily at D-3 (3 days before initial dose of SPOT-mRNA03) for 4 weeks. All subjects are first administered via intravenous infusion on D1 and then administered twice a week (once every 4 days) for a total of 8 doses.

Four weeks after the initial administration of the subjects in the previous dose cohort, if there are no serious adverse events related to the treatment, it will be determined that the subjects in next dose cohort could be administered after discussion between the investigators and the sponsor. Safety evaluations on subjects are conducted during each administration and follow-up.

Enrollment: 6 estimated patients

Sex: Male

Ages: 2 to 6 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. According to the requirements of the region/country and/or IRB/IEC, the patient and/or legal guardian have signed a written informed consent form and are aware of all relevant study content.

2. Ambulatory boys aged between 2 to 6 years of age, inclusive who can work without assistance for at least 10 meters.

3. The medical history includes clinical diagnosis of DMD and confirmed Duchenne mutations using validated genetic testing (MLPA and whole genome sequencing).

4. Able to tolerate muscle biopsy under anesthesia and have no contraindications to biopsy.

5. Heart, liver, lung, and kidney functions are sufficient:

   1. The left ventricular ejection fraction (LVEF) should be ≥ 50%;
   2. Forced vital capacity (FVC) > 50% of the expected value, and do not require nighttime ventilation;
   3. Patient's glomerular filtration rate (GFR)>30 mL/min/1.73 m2

Exclusion criteria

1. Complications other than DMD that may cause muscle weakness and/or motor dysfunction.

2. There are severe intellectual disabilities (such as severe autism, severe cognitive impairment, and severe behavioral disorders) that, according to the investigator's judgment, can affect the study.

3. Hospitalization for respiratory failure within 8 weeks prior to screening.

4. Asthma or underlying lung diseases that are poorly controlled, such as bronchitis, bronchiectasis, emphysema, or recurrent infectious pneumonia that investigator believes may affect respiratory function.

5. Severe uncontrolled heart failure (NYHA III-IV), including any of the following conditions：

   1. Intravenous administration of diuretics or positive inotropic drugs is required within 8 weeks prior to screening.
   2. Hospitalization due to worsening heart failure or arrhythmia within 8 weeks prior to screening.

6. Abnormal laboratory values considered clinically significant:

   1. GGT > 3 × upper limit of normal
   2. Bilirubin ≥ 3.0 mg/dL
   3. Creatinine ≥ 1.8 mg/dL
   4. Hemoglobin < 8 or > 18 g/dL
   5. White blood cell count > 18,500/μL

7. Arrhythmias that require anti-arrhythmic treatment.

8. Subjects who are undergoing immunosuppressive therapy.

9. Has used other gene therapy, investigational drugs, or any treatment aimed at increasing dystrophin expression.

10. Subjects with a history of major surgeries within 12 weeks prior to the initial infusion or planning to undergo major surgeries (such as scoliosis surgery) during this study.

11. Subjects who are allergic to investigational products or local aesthetic drugs or have a history of severe allergies or genetic allergic reactions.

12. Within 6 months prior to the initial infusion, the subjects are exposed to another investigational drug or have participated in an intervention clinical trial.

13. Subjects with positive hepatitis B core antibody or hepatitis C antibody or HIV antibody during screening.

14. Investigator believes that the presence of any other serious diseases, medical conditions, or chronic drug treatment needs can pose unnecessary risks to gene transfer.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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6 participants in 1 patient group

Low Dose and High Dose

Other group

Description:

3 patients will be administered with low dose and 3 patients will be administered with high dose

Treatment:

Genetic: mRNA