Bionos Biotech SL, Biopolo Hospital La Fe, 46026 Valencia, Spain.
Departamento de Química Orgánica e Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, 46980 Valencia, Spain.
Int J Mol Sci. 2023 Oct 13;24(20):15153. doi: 10.3390/ijms242015153.
Huntington's disease (HD) is an inherited neurodegenerative disorder considered a rare disease with a prevalence of 5.7 per 100,000 people. It is caused by an autosomal dominant mutation consisting of expansions of trinucleotide repeats that translate into poly-glutamine enlarged mutant huntingtin proteins (mHTT), which are particularly deleterious in brain tissues. Since there is no cure for this progressive fatal disease, searches for new therapeutic approaches are much needed. The small molecule pytren-4QMn (4QMn), a highly water-soluble mimic of the enzyme superoxide dismutase, has shown in vivo beneficial anti-inflammatory activity in mice and was able to remove mHTT deposits in a C. elegans model of HD. In this study, we assessed 4QMn therapeutic potential in zQ175 neo-deleted knock-in mice, a model of HD that closely mimics the heterozygosity, genetic injury, and progressive nature of the human disease. We provide evidence that 4QMn has good acute and chronic tolerability, and can cross the blood-brain barrier, and in male, but not female, zQ175 mice moderately ameliorate HD-altered gene expression, mHtt aggregation, and HD disease phenotype. Our data highlight the importance of considering sex-specific differences when testing new therapies using animal models and postulate 4QMn as a potential novel type of small water-soluble metal complex that could be worth further investigating for its therapeutic potential in HD, as well as in other polyglutamine diseases.
亨廷顿病（HD）是一种遗传性神经退行性疾病，被认为是一种罕见病，其患病率为每 10 万人中有 5.7 人。它是由常染色体显性突变引起的，突变由三核苷酸重复扩展组成，导致多谷氨酰胺扩增的突变 huntingtin 蛋白（mHTT），这些蛋白在脑组织中特别有害。由于这种进行性致命疾病尚无治愈方法，因此非常需要寻找新的治疗方法。小分子 pytren-4QMn（4QMn）是一种超氧化物歧化酶的高度水溶性模拟物，已在体内显示出对小鼠有益的抗炎活性，并能够去除 HD 线虫模型中的 mHTT 沉积物。在这项研究中，我们评估了 4QMn 在 zQ175 neo-缺失敲入小鼠中的治疗潜力，zQ175 neo-缺失敲入小鼠是一种模拟人类疾病异质性、遗传损伤和进行性的 HD 模型。我们提供的证据表明，4QMn 具有良好的急性和慢性耐受性，可穿过血脑屏障，并且在雄性但不是雌性 zQ175 小鼠中适度改善 HD 改变的基因表达、mHtt 聚集和 HD 疾病表型。我们的数据强调了在使用动物模型测试新疗法时考虑性别差异的重要性，并假设 4QMn 是一种新型的小水溶性金属配合物，可能具有进一步研究其在 HD 以及其他多谷氨酰胺疾病中的治疗潜力的价值。
