Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

Abstract

SummaryLate infantile neuronal ceroid lipofuscinosis (LINCL), a fatal autosomal recessive neurodegenerative lysosomal storage disorder of childhood, is caused by mutations in the CLN2 gene, resulting in deficiency of the protein tripeptidyl peptidase I (TPP-I). We have previously shown that direct CNS administration of AAVrh.10hCLN2 to adult CLN2 knockout mice, a serotype rh.10 adeno-associated virus expressing the wild type CLN2 cDNA, will partially improve neurological function and survival. In this study, we explore the hypothesis that administration of AAVrh.10hCLN2 to the neonatal brain will significantly improve the results of AAVrh.10hCLN2 therapy. To assess this concept, AAVrh.10hCLN2 vector was administered directly to the CNS of CLN2 knockout mice at 2 days, 3 wk and 7 wk of age. While all treatment groups show a marked increase in total TPP-I activity over wild-type mice, neonatally treated mice displayed high levels of TPP-I activity in the CNS 1 yr after administration which was spread throughout the brain. Using behavioral markers, 2 day treated mice demonstrate marked improvement over 3 wk, 7 wk or untreated mice. Finally, neonatal administration of AAVrh.10hCLN2 was associated with markedly enhanced survival, with a median time of death 376 days for neonatal treated mice, 277 days for 3 wk treated mice, 168 days for 7 wk treated mice, and 121 days for untreated mice. These data suggest that neonatal treatment offers many unique advantages, and that early detection and treatment may be essential for maximal gene therapy for childhood lysosomal storage disorders affecting the CNS.

Comparative Efficacy and Safety of Multiple Routes of Direct CNS Administration of Adeno-Associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human Arylsulfatase A cDNA to Nonhuman Primates

“…For direct CNS gene therapy, AAV vectors have emerged as the most promising clinical vector because of their excellent safety and efficacy profile (Sevin et al, 2007;Sondhi et al, 2008). AAV-based therapies to the CNS have been assessed in Canavan, late infantile neuronal ceroid lipofuscinosis (LINCL), Alzheimer's, and Parkinson's diseases ( Janson et al, 2002;Tuszynski and Blesch, 2004;McPhee et al, 2006;Kaplitt et al, 2007;Worgall et al, 2008;Mandel, 2010;Souweidane et al, 2010;Kells et al, 2012).…”

Partial Correction of the CNS Lysosomal Storage Defect in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis by Neonatal CNS Administration of an Adeno-Associated Virus Serotype rh.10 Vector Expressing the Human CLN3 Gene

“…Neonatal administration of therapeutic vectors takes advantage of the maximum plasticity of the brain and of the immature immune system, giving the maximum impact on phenotype; it also provides the opportunity for an early therapeutic intervention before the onset of overt pathology (Daly et al, 1999b;Waddington et al, 2004;Sondhi et al, 2008). These data demonstrate that expression of a human-derived transgene from an AAVrh.10 vector administered to the brain of neonatal mice is readily detected at 16-18 months of age.…”

Gene Therapy Approaches for Lysosomal Storage Disease: Next-Generation Treatment

“…As LSDs are progressive diseases, it has been shown that the longer the duration of disease, combined with the inherent reduction in tissue plasticity with age, the less chance there is to reverse pathology. Neonatal gene transfer has been successful with RV, LV, and rAAV vectors in several preclinical animal models of LSDs including MPS I, MPS VII, Fabry, Batten, and Pompe disease (Meikle and Hopwood, 2003;Rucker et al, 2004;Yoshimitsu et al, 2004;Mah et al, 2007;Traas et al, 2007;Sondhi et al, 2008). How neonatal gene therapy will translate clinically is yet unknown, because in the neonatal stage humans have a more developed or mature immune system compared with lesser animals.…”