There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687.

有超过 10,000 种罕见疾病，而且大多数都无法治疗。个性化基因治疗代表了一种有前途的治疗方法。我们通过建立针对 50 型遗传性痉挛性截瘫 (SPG50) 单一患者开发的基因替代疗法，提出了一种超罕见疾病的个体化治疗路线图。通过多中心合作，创建了一种携带 AP4M1 基因的基于腺相关病毒的基因治疗产品，并作为单患者 1 期试验的一部分，在诊断后 3 年内成功对一名 4 岁患者进行了鞘内注射。主要终点是安全性和耐受性，次要终点评估疗效。给药 12 个月后，该疗法的耐受性良好。没有观察到严重的不良事件，有一些轻微的事件，包括暂时性中性粒细胞减少症和艰难梭菌胃肠炎，但已得到解决。初步疗效测量表明病程稳定。需要更长时间的随访来确认安全性并提供有关治疗效果的更多见解。总体而言，该报告支持 SPG50 基因治疗的安全性，并为罕见疾病的精准治疗开发提供了见解。临床试验注册号：NCT06069687。