An Investigator-initiated Clinical Study Evaluating the CRISPR-hfCas12Max Gene Editing Therapy in the Treatment of Duchenne Muscular Dystrophy (DMD)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Incidence and severity of systemic adverse events
研究概览
简要总结
Duchenne muscular dystrophin (DMD) is an X-linked, fatal muscle-wasting disease caused by mutations in the DMD gene encoding the dystrophin proteins, with symptom onset before age of 6 years in boys. These mutations abolish dystrophin production in the muscle, leading to dystrophin deficiency at the myofiber membrane, continued fiber degeneration, the need for assisted ventilation, respiratory inflammation, loss of walking ability in their teens, followed by respiratory and cardiac decline, and eventually premature death before the age of 30.
Currently, there are only glucocorticoids for the standard supportive therapy of DMD, which can improve disease symptoms but do not change the outcome of the disease, Three antisense oligonucleotide (ASOs) medicines have been approved to treat DMD with exon 45-55 hotspot region mutations. However, they can only restore trace amounts of dystrophin protein, which is insufficient to bring real clinical benefits. Gene replacement therapy has been approved using adeno-associated virus (AAV) vectors to deliver the "mini-dystrophin" gene. Yet, mini-dystrophin gene-expression versions of truncated dystrophin functionality are sacrificed and limited.
HG302 uses a single AAV vector to deliver the CRISPR/hfCas12Max DNA editing system in the human DMD exon 51 splice donor site. Preclinical studies have shown that a single intravenous injection of HG302 significantly restores dystrophin protein expression in muscle fibers and rescues their muscle function in humanized DMD mice to wild-type levels, with long-lasting and durable efficacy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Years 至 8 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Males ≥ 4 and ≤8 years at the time of signing informed consent, with clinical diagnosis of DMD;
- •DMD gene mutation types are deletions in exons 52, 52-61, or 52-63;
- •Able to walk at least 10 meters independently;
- •Willing to cooperate with muscle biopsy test;
- •Acceptable hematology, clinical chemistry, and urine laboratory parameters.
排除标准
- •Presence of active infection;
- •Presence of DMD-associated cardiomyopathy manifestations;
- •Respiratory insufficiency requiring invasive or non-invasive ventilation;
- •Serious infections such as pneumonia, pyelonephritis, or meningitis within 4 weeks prior to receiving trial drug infusion;
- •Prior central nervous system surgery within 6 months before enrolment;
- •Use of any investigational drug, or exon-skipping drug (whether investigational or not) 6 months prior to Screening;
- •Previous treatment with any gene therapy or cell therapy (e.g., stem cell transplantation);
- •Any other conditions that would not allow the potential subject to complete follow-up examinations during the study and would, in the opinion of the investigator, make the potential subject unsuitable for the study.
研究组 & 干预措施
HG302
The study will enroll up to 2 dose cohorts
干预措施: HG302 (Genetic)
结局指标
主要结局
Incidence and severity of systemic adverse events
时间窗: 26 weeks
Number of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs)
次要结局
- Change from baseline in percentage of dystrophin positive fiber(26 weeks)
- Change from baseline in dystrophin fiber intensity(26 weeks)
- Change from baseline in North Star Ambulatory Assessment scale(26 weeks)
- Change from baseline in dystrophin expression in skeletal muscle (western blotting)(26weeks)
- Change from baseline in North Star Ambulatory Assessment scale and 6 minutes' walk test(26 weeks)