Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: a long-term follow-up pilot study
image: Genetically modified hematopoietic stem cells to treat symptomatic juvenile MLD patients with long-term follow-up study.
Credit: Zhao Zhang, Hua Jiang, Li Huang, Sixi Liu, Xiaoya Zhou, Yun Cai, Ming Li, Fei Gao, Xiaoting Liang, Kam-Sze Tsang, Guangfu Chen, Chui-Yan Ma, Yuet-Hung Chai, Hongsheng Liu, Chen Yang, Mo Yang, Xiaoling Zhang, Shuo Han, Xin Du, Ling Chen, Wuh-Liang Hwu, Jiacai Zhuo, Qizhou Lian
Metachromatic leukodystrophy (MLD) is a rare genetic disorder caused by the deficiency of arylsulfatase A (ARSA) or its activator prosaposin (PSAP). This leads to the accumulation of sulfatides in the nervous system, causing demyelination, neuroinflammation, and neurodegeneration. MLD is classified into three subtypes based on the age of symptom onset: late infantile (0–2.5 years), juvenile (2.5–18 years), and adult (after 18 years). The disease progresses more rapidly in late infantile and juvenile MLD, often leading to severe motor and cognitive decline and death within a few years.
Traditional treatments such as ARSA enzyme replacement therapy and intracerebral adeno-associated virus gene therapy have shown limited efficacy in halting disease progression, especially in advanced symptomatic stages. Allogeneic hematopoietic stem cell transplantation (HSCT) has been effective in presymptomatic juvenile MLD but is limited by rapid disease progression, a lack of HLA-matched donors, and other complications.
This pilot study aimed to evaluate the safety and efficacy of lentivirus-modified hematopoietic stem cell gene therapy (HSCGT) in patients with advanced symptomatic juvenile MLD. The study included a long-term follow-up to assess the outcomes of the therapy.
Key findings from the study include:
- Safety of HSCGT: The study demonstrated that lentivirus-modified hematopoietic stem cell gene therapy is safe for patients with advanced symptomatic juvenile MLD. No significant adverse events were reported, and the therapy was well-tolerated.
- Clinical Benefits: Patients who received HSCGT showed improvements in motor and cognitive functions. The therapy slowed the progression of the disease, leading to better quality of life for the patients. Specifically, there was a reduction in the rate of demyelination and neuroinflammation.
- Long-term Follow-up: The long-term follow-up of the patients indicated sustained clinical benefits. The therapy not only provided immediate relief but also maintained its effectiveness over time, suggesting a potential cure for the disease.
- Comparison with Traditional Treatments: Unlike traditional treatments, HSCGT was effective even in advanced symptomatic stages of the disease. This is a significant improvement, as other therapies have shown limited efficacy in these stages.
- Feasibility and Accessibility: The study highlighted the feasibility of using lentivirus-modified HSCGT in clinical settings. The therapy can be administered to patients who do not have access to HLA-matched donors, expanding the treatment options for MLD.
The study on lentivirus-modified hematopoietic stem cell gene therapy (HSCGT) for advanced symptomatic juvenile metachromatic leukodystrophy (MLD) provides compelling evidence of its safety and efficacy. The therapy not only halted the progression of the disease but also improved motor and cognitive functions in the patients. The long-term follow-up confirmed the sustained benefits of HSCGT, making it a promising treatment option for MLD, especially in cases where traditional therapies have failed. The findings suggest that HSCGT could potentially offer a cure for MLD and should be further explored in larger clinical trials. The work entitled “ Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: a long-term follow-up pilot study” was published on Protein & Cell (published on Jun. 25, 2024).