O17: Exploring MED27 gene pathogenicity in a neurodevelopmental disorder with cerebellar atrophy

remained elevated at ~12 fold over endogenous murine Naa10 in the high dose group (~10 fold in med.dose, and 1.6-fold in the low dose group).Dose dependent expression of the vector was also observed in liver at 24 weeks, but at much lower levels than in brain.In addition, expression of endogenous Naa10 did not change in response to overexpression of the AAV vector in either brain or liver suggesting that the expression of this AAV does not interfere with normal gene regulation of this locus.We have also created an improved mouse model of OS with one of the most prevalent variants (Arg83Cys).This R83C strain has a similar phenotype (albeit less penetrant) to the Naa10 knockout, thus favoring the mechanism of reduced NTA of key proteins.We previously showed that mice have a compensating enzyme Naa12 that is not present in humans, thus enabling the Naa10 knockout and Naa10 R83C mice to survive embryogenesis.Nonetheless, extensive cognitive testing of male Naa10 knockout mice revealed profound learning and memory deficits.We bred the Naa12 knockout mice to the Naa10 knockout and Naa10 R83C strains, and the Naa10 Arg83Cys/y Naa12 +/-double mutant males are born, but at a much lower rate and exhibit reduced size, small head, upturned nose, small testes, and reduced adipose tissue.Heterozygous Naa10 Arg83Cys/+ Naa12 +/-and double mutant Naa10 Arg83Cys/+ Naa12 -/-females both survive to birth but have milder phenotypes than males.Conclusion: Overall, we have developed an improved mouse model for OS and made substantial progress toward preclinical development of an AAV9-NAA10 gene therapy for OS.