Intrathecal delivery of AAV-NDNF ameliorates disease progression of ALS mice

• Published in: Molecular therapy 2023-11, Vol.31 (11), p.3277-3289
• Main Authors: Cheng, Wei, Huang, Jing, Fu, Xiu-Qing, Tian, Wei-Ya, Zeng, Peng-Ming, Li, Yang, Luo, Zhen-Ge
• Format: Article
• Language: English
• Subjects: adeno-associated virus; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - therapy; Animals; Dependovirus - genetics; Disease Models, Animal; Disease Progression; Mice; Mice, Transgenic; motor behavior; motor neuron loss; Motor Neurons - metabolism; Nerve Growth Factors - metabolism; Neurodegenerative Diseases - metabolism; neuron-derived neurotrophic factor; neuronal degeneration; Original; Spinal Cord - metabolism; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.09.018

Amyotrophic lateral sclerosis (ALS) is a uniformly lethal neurodegenerative disease characterized by progressive deterioration of motor neurons and neuromuscular denervation. Adeno-associated virus (AAV)-mediated delivery of trophic factors is being considered as a potential disease-modifying therapeutic avenue. Here we show a marked effect of AAV-mediated over-expression of neuron-derived neurotrophic factor (NDNF) on SOD1G93A ALS model mice. First, we adopt AAV-PHP.eB capsid to enable widespread expression of target proteins in the brain and spinal cord when delivered intrathecally. Then we tested the effects of AAV-NDNF on SOD1G93A mice at different stages of disease. Interestingly, AAV-NDNF markedly improved motor performance and alleviated weight loss when delivered at early post-symptomatic stage. Injection in the middle post-symptomatic stages still improved the locomotion ability, although it did not alleviate the loss of body weight. Injection in the late stage also extended the life span of SOD1G93A mice. Furthermore, NDNF expression promoted the survival of spinal motoneurons, reduced abnormal protein aggregation, and preserved the innervated neuromuscular functions. We further analyzed the signaling pathways of NDNF expression and found that it activates cell survival and growth-associated mammalian target of rapamycin signaling pathway and downregulates apoptosis-related pathways. Thus, intrathecally AAV-NDNF delivery has provided a potential strategy for the treatment of ALS. [Display omitted] Luo and colleagues demonstrate a beneficial effect of AAV-mediated expression of the less studied neurotrophic factor NDNF on disease progression of ALS model mice. It holds promise as a potential disease-modifying strategy for ALS treatment.