A Clinical Study Evaluating the Safety, Tolerability, and Initial Efficacy of JWK008 Given by a Single Intravenous Infusion in Patients With Mucopolysaccharidosis Type I
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- adverse events
研究概览
简要总结
This study is a single-center, single-arm, non-randomized, open-label, non controlled, dose-escalation, prospective clinical trial designed to assess the safety, tolerability, and preliminary efficacy of JWK008 injection in patients with MPS I.
详细描述
MPS I is a rare autosomal recessive disease caused by deficiency of the α-L-iduronidase (IDUA) gene, which encodes a lysosomal enzyme required for degradation of glycosaminoglycans (GAGs).While currently available therapies, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), provide clinical benefit over untreated disease progression,they still have significant limitations. ERT does not cross the blood-brain barrier and, therefore, does not treat the central nervous system (CNS) effects of the disease. And HSCT, although it can prevent cognitive decline in patients, has a high mortality rate and morbidity. The investigators have designed a novel IDUA fusion protein with the ability to cross the blood-brain barrier through the addition of the brain-targeting peptide Mtfp. On this basis, the investigators constructed an IDUA gene expression cassette for liver-targeted expression, and used a highly efficient liver-specific promoter to make the IDUA gene specifically and efficiently expressed in liver tissue, and the expressed protein can enter the central nervous system to exert therapeutic effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age≥ 18 years old;
- •Diagnosis of MPS type I;
- •Be able to understand the purpose, content, and possible risks of this clinical study, voluntarily participate in and sign the informed consent form;
- •If the subject is female, her sexual partner must agree to use reliable contraception until 2 consecutive tests of vector sequence in the blood are negative; If the subject is male, the subject agrees to use reliable contraception until the semen sample is negative for 2 consecutive tests of the vector sequence.
- •Magnetic resonance imaging (MRI) of the liver mass read by the radiologist is negative.
排除标准
- •Known to be unresponsive to ERT; or those who have been treated with intrathecal or intravenous laronidase and have serious adverse reactions, such as significant infusion-related reactions (IARs) or anaphylactic shock.
- •Serum AAV5 neutralizing antibody titer is greater than 1:
- •Has contraindications for Corticosteroids.
- •Current treatment with systemic (intravenous or oral) immunomodulators or steroid use (topical treatments such as asthma or eczema are allowed).
- •Has contraindications for lumbar puncture.
- •When filtering, one of the following situations exists:
- •Hepatitis B surface antigen (HBsAg) is positive, and the copy number of hepatitis B virus deoxyribonucleic acid (HBV-DNA) is>the upper limit of normal value (ULN);
- •Hepatitis C virus antibody (HCV-Ab) is positive, and the copy number of hepatitis C virus ribonucleic acid (HCV-RNA) is>ULN;
- •Receiving antiviral treatment for hepatitis B or C;
- •The human immunodeficiency virus (HIV) test is positive and the CD4+T lymphocyte count is ≤ 200/mm3;
- •Abnormal laboratory values considered clinically significant (ALT and/or AST >3× upper limit of normal (ULN), total bilirubin > 1.5× ULN, serum creatinine > 1.5× ULN, etc.).
- •Have a history of chronic infections or other chronic diseases that researchers believe pose an unacceptable risk;
- •Active severe infection or any other significant accompanying, uncontrolled medical condition(except for those caused by MPS I), including but not limited to kidney, liver, blood, gastrointestinal, endocrine, lung, nervous system, brain or mental illness, alcoholism, drug dependence, or any psychological disorder assessed by the researcher that may interfere with adherence to experimental protocol procedures or tolerance to JWK008 injection;
- •History of active malignancy within the past 5 years (non-melanotic skin cancer or carcinoma in situ of the cervix is allowed).
- •Circulating alpha-fetoprotein (AFP) is elevated or abnormal.
- •Previously received gene therapy or participated in interventional clinical studies within the past 12 weeks;
- •Pregnant or lactating females.
- •The researcher believes that the subject is not suitable to participate in any concurrent clinically significant major diseases or other situations in the study;
- •Unable or unwilling to comply with the visit and study evaluation schedule described in the clinical protocol.
结局指标
主要结局
adverse events
时间窗: 5 years
Adverse events defined as the number of participants with adverse events according CTCAE 5.0
次要结局
- IDUA enzyme activity in blood and cerebrospinal fluid(5 years)
- GAG levels in blood, urine, and cerebrospinal fluid(5 years)
- Six-Minute Walk Test(5 years)
- Liver and spleen size were detected by CT(5 years)
- Range of the joint motion(JROM) testing by measuring ruler(5 years)
- Vector shedding(5 years)
研究者
Xingchen Peng
PhD, Professor
West China Hospital