The therapeutic potential of laquinimod for Huntington’s disease: A systematic review of preclinical and clinical studies

Neuroinflammation is a central contributor to Huntington’s disease (HD) pathogenesis and represents a promising therapeutic target. Laquinimod, an oral immunomodulator with demonstrated neuroprotective effects in preclinical models, has been investigated as a potential treatment for HD. This review critically appraises its preclinical and clinical evidence. A systematic search (January 2025) was conducted in PubMed, Scopus, Embase, Cochrane Library, and Web of Science using terms including “Huntington’s disease,” “laquinimod,” and “quinoline-3-carboxylic acid.” Preclinical and clinical studies evaluating laquinimod in HD were included. Due to heterogeneity, findings were synthesized qualitatively. Of 2638 records identified, 10 studies met the inclusion criteria. Preclinical data showed laquinimod improved motor function, reduced neuroinflammation, and promoted myelination, likely via microglial modulation, NF-κB suppression, and increased BDNF expression. Effects on myelin integrity and inflammatory markers were inconsistent. In vitro studies showed limited, variable cytokine modulation in HD patient-derived cells. Clinical trials did not demonstrate significant improvements in motor or functional outcomes, though one study reported minor cognitive and behavioral benefits. Preclinical evidence suggests laquinimod may modulate motor, inflammatory, and myelination pathways in HD; however, clinical evidence shows no meaningful benefit. Data on long-term safety remain limited. Larger, well-designed trials using standardized biomarkers are needed to clarify its therapeutic potential. Huntington’s disease (HD) is an inherited brain condition that affects movement, thinking, and mood. Current treatments help with symptoms but cannot stop the disease from getting worse. Laquinimod is a pill that changes how the immune system works and may protect brain cells. Studies in mice with HD showed that laquinimod could improve movement, reduce brain inflammation, and protect nerve cells. Laboratory studies using human cells found that laquinimod could reduce some inflammatory signals, but the effects were weaker and varied. In people with HD, laquinimod was generally safe but did not clearly improve movement, thinking, or daily activities. Some small benefits were seen in a few tests, but they were inconsistent. Overall, laquinimod shows promise in lab and animal studies, but current evidence in humans does not show clear benefits. More research is needed to see if it could help when given at the right dose or early in the disease.神经炎症（Neuroinflammation）是亨廷顿舞蹈病（Huntington’s disease, HD）发病机制的核心诱因，亦是极具潜力的治疗靶点。拉喹莫德（Laquinimod）作为一种已在临床前模型（preclinical models）中证实具有神经保护作用的口服免疫调节剂，已被研究作为HD的潜在治疗手段。本综述对其临床前与临床证据进行了批判性评估。 研究团队于2025年1月在PubMed、Scopus、Embase、Cochrane Library及Web of Science数据库开展系统检索，检索词包括"Huntington’s disease"、"laquinimod"及"喹啉-3-羧酸（quinoline-3-carboxylic acid）"。最终纳入评估拉喹莫德用于HD的临床前及临床研究。鉴于研究异质性，研究结果采用定性综合分析。 本次检索共识别出2638条文献记录，其中10项研究符合纳入标准。临床前数据显示，拉喹莫德可改善运动功能、减轻神经炎症并促进髓鞘形成，其潜在机制可能涉及小胶质细胞调控（microglial modulation）、核因子κB（NF-κB）抑制及脑源性神经营养因子（BDNF）表达上调。不过其对髓鞘完整性与炎症标志物的研究结果存在不一致性。体外实验（in vitro studies）显示，拉喹莫德对HD患者来源细胞的细胞因子调控作用有限且存在差异。临床试验未观察到运动或功能结局的显著改善，不过有一项研究报告了轻微的认知与行为获益。 临床前证据表明，拉喹莫德或可通过调控运动、炎症及髓鞘形成通路以干预HD进程；但临床证据并未显示其具有明确获益。其长期安全性数据仍较为有限。未来需开展更大样本量、设计严谨且采用标准化生物标志物（standardized biomarkers）的临床试验，以明确其治疗潜力。 亨廷顿舞蹈病（HD）是一种遗传性脑部疾病，可影响运动、认知与情绪功能。现有治疗手段仅能改善症状，无法延缓疾病进展。拉喹莫德是一种可调节免疫系统的口服制剂，或可保护神经细胞。HD模型小鼠实验显示，拉喹莫德可改善运动功能、减轻脑部炎症并保护神经细胞。采用人类细胞开展的实验室研究发现，拉喹莫德可降低部分炎症信号，但作用较弱且存在个体差异。在HD患者中，拉喹莫德总体安全性良好，但未明确改善运动、认知或日常活动能力。少数试验观察到轻微获益，但结果并不一致。 总体而言，拉喹莫德在实验室与动物实验中展现出治疗潜力，但当前人体研究并未显示明确获益。未来需开展更多研究，以明确其在适宜剂量或疾病早期给药时是否具有临床获益。