AAV-based gene therapy ameliorates neurological deficits in a mouse model of childhood-onset neurodegeneration with cerebellar atrophy.

Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is an autosomal recessive pediatric disorder caused by biallelic mutations in the ATP/GTP-binding protein 1 gene, which encodes cytosolic carboxypeptidase 1 (CCP1) with deglutamylase activity. These patients typically exhibit progressive motor and cognitive impairment, often leading to childhood mortality. Despite its severe clinical course, no effective treatments have been developed. In this study, we demonstrate the efficacy of gene therapy using adeno-associated virus (AAV) vectors to deliver a functional mouse Ccp1 mutant in a Ccp1-deficient mouse model of CONDCA. Expression of the N-terminally truncated form of Ccp1 (Ccp1Δ1), which retains deglutamylase activity, in neurons of Ccp1-deficient neonatal mice via a blood-brain barrier-penetrating AAV vector strongly prevented Purkinje cell degeneration during postnatal development. Furthermore, gene therapy using Ccp1Δ1 partially, albeit significantly, improved motor functions in these mice, notably enhancing voluntary gait stability. This study provides robust preclinical evidence supporting the potential of postnatal AAV gene therapy as a treatment strategy for CONDCA.