Capsid-Engineering for Central Nervous System-Directed Gene Therapy with Adeno-Associated Virus Vectors.

Closing the gap in knowledge on the cause of neurodegenerative disorders is paving the way toward innovative treatment strategies, among which gene therapy has emerged as a top candidate. Both conventional gene therapy and genome editing approaches are being developed, and a great number of human clinical trials are ongoing. Already 2 years ago, the first gene therapy for a neurodegenerative disease, spinal muscular atrophy type 1 (SMA1), obtained market approval.

Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function.

Heterozygous de novo mutations in EEF1A2, encoding the tissue-specific translation elongation factor eEF1A2, have been shown to cause neurodevelopmental disorders including often severe epilepsy and intellectual disability. The mutational profile is unusual; ~50 different missense mutations have been identified but no obvious loss of function mutations, though large heterozygous deletions are known to be compatible with life. A key question is whether the heterozygous missense mutations operate through haploinsufficiency or a gain of function mechanism, an important prerequisite for design of therapeutic strategies.