Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Sci Transl Med. 2014 Apr 9;6(231):231ra48. doi: 10.1126/scitranslmed.3007733.
Progressive debilitating neurological defects characterize feline G(M1) gangliosidosis, a lysosomal storage disease caused by deficiency of lysosomal β-galactosidase. No effective therapy exists for affected children, who often die before age 5 years. An adeno-associated viral vector carrying the therapeutic gene was injected bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of a feline model of G(M1) gangliosidosis. Gene therapy normalized β-galactosidase activity and storage throughout the brain and spinal cord. The mean survival of 12 treated G(M1) animals was >38 months, compared to 8 months for untreated animals. Seven of the eight treated animals remaining alive demonstrated normalization of disease, with abrogation of many symptoms including gait deficits and postural imbalance. Sustained correction of the G(M1) gangliosidosis disease phenotype after limited intracranial targeting by gene therapy in a large animal model suggests that this approach may be useful for treating the human version of this lysosomal storage disorder.
进行性神经功能缺陷是猫 GM1 神经节苷脂贮积症的特征，该病是一种溶酶体贮积病，由溶酶体β-半乳糖苷酶缺乏引起。目前尚无有效的治疗方法，受影响的儿童通常在 5 岁前死亡。携带治疗基因的腺相关病毒载体被双侧注射到 GM1 神经节苷脂贮积症猫模型的两个脑靶标（丘脑和小脑深部核）中。基因治疗使大脑和脊髓中的β-半乳糖苷酶活性和贮积恢复正常。12 只接受治疗的 GM1 动物的平均存活时间超过 38 个月，而未接受治疗的动物为 8 个月。在大型动物模型中，通过基因治疗对颅内有限靶标进行治疗后，8 只存活的治疗动物中有 7 只疾病得到了正常化，许多症状得到了缓解，包括步态缺陷和姿势平衡失调。在大型动物模型中，通过基因治疗对颅内有限靶标进行治疗后，GM1 神经节苷脂贮积症的疾病表型得到持续纠正，这表明该方法可能对治疗人类版这种溶酶体贮积障碍有用。
