Venkataraman Lalitha, Jeanty Christopher J, Kaniganti Tarun, Kennedy Benjamin J, Sullivan Patricia, Goldstein David S, Kaler Stephen G
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Sci Adv. 2025 Aug 29;11(35):eadw5612. doi: 10.1126/sciadv.adw5612.
Menkes disease is an X-linked recessive condition characterized by seizures, failure to thrive, and rapid, progressive neurodegeneration beginning within weeks after birth. Death usually occurs by 3 years of age. The disorder is caused by genetic variants in , an evolutionarily conserved copper transporter that is crucial for normal brain development. The mouse recapitulates salient features of the human illness. Affected male mice typically die by 14 postnatal days. We evaluated a single-dose intravenous adeno-associated virus gene therapy approach to deliver working copies of a codon-optimized version of ATP7A to male mice. In conjunction with subcutaneous injections of clinical-grade copper histidinate in the first month of life, 95% long-term survival was attained, which was correlated with improvements in serum and brain copper levels, brain neurochemical profiles, somatic growth, and neuromotor function. The notable results support a trial of this treatment combination in affected male newborns with Menkes disease.
门克斯病是一种X连锁隐性疾病，其特征为癫痫发作、生长发育迟缓，以及出生后数周内开始的快速、进行性神经退行性变。通常在3岁前死亡。该疾病由ATP7A基因的遗传变异引起，ATP7A是一种在进化上保守的铜转运蛋白，对正常脑发育至关重要。Atp7a基因敲除小鼠概括了人类疾病的显著特征。受影响的雄性小鼠通常在出生后14天内死亡。我们评估了一种单剂量静脉注射腺相关病毒基因治疗方法，将密码子优化版ATP7A的功能性拷贝递送至雄性Atp7a基因敲除小鼠体内。在出生后的第一个月，结合皮下注射临床级组氨酸铜，实现了95%的长期存活率，这与血清和脑铜水平、脑神经化学特征、身体生长和神经运动功能的改善相关。这些显著结果支持在患有门克斯病的受影响雄性新生儿中对这种治疗组合进行试验。
