Aspa, encoding aspartoacylase, is a key gene whose product hydrolyzes N-acetylaspartate (NAA) to acetate and aspartate [1,2]. Mutations in the Aspa gene are associated with Canavan disease, an autosomal recessive leukodystrophy [1,2,3]. The normal function of Aspa is crucial for maintaining proper metabolism in the central nervous system.

In Canavan disease research, introducing the wild-type Aspa gene into patient-derived induced pluripotent stem cells (iPSCs) via lentiviral transduction or Nuclease technology-mediated gene editing, and then differentiating them into neural progenitor cells (NPCs), led to potent Aspa enzymatic activity [1]. These ASPA-CD NPCs could survive in the brains of transplanted CD mice, reconstituting Aspa activity, reducing the elevated NAA level in brain tissues and cerebrospinal fluid, and rescuing pathological phenotypes like spongy degeneration, myelination defects, and motor function impairment [1]. A similar feline neurodegenerative disease was also found to be associated with a mutation in the Aspa gene [2].

In conclusion, Aspa is essential for the normal metabolism of NAA in the central nervous system. The study of Aspa-related gene therapies using iPSCs and mouse models has provided valuable insights into the treatment of Canavan disease, highlighting the importance of Aspa in maintaining neurological function and the potential of genetic-based approaches for this devastating neurological disorder [1,2].

References:

1. Chao, Jianfei, Feng, Lizhao, Ye, Peng, Matalon, Reuben, Shi, Yanhong. 2022. Therapeutic development for Canavan disease using patient iPSCs introduced with the wild-type ASPA gene. In iScience, 25, 104391. doi:10.1016/j.isci.2022.104391. https://pubmed.ncbi.nlm.nih.gov/35637731/

2. Takaichi, Yuta, Chambers, James K, Shiroma-Kohyama, Moeko, Nakayama, Hiroyuki, Uchida, Kazuyuki. 2021. Feline Spongy Encephalopathy With a Mutation in the ASPA Gene. In Veterinary pathology, 58, 705-712. doi:10.1177/03009858211002176. https://pubmed.ncbi.nlm.nih.gov/33779415/

3. Yalcintepe, Sinem, Maras, Tuba, Kizilyar, Ilke, Ozen, Yasemin, Gurkan, Hakan. 2024. Homozygous Paternally Inherited ASPA Variant in a Patient with Canavan Disease. In Molecular syndromology, 15, 284-288. doi:10.1159/000536386. https://pubmed.ncbi.nlm.nih.gov/39119446/