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AAV9-Mediated Gene Therapy In A Knock-In Mouse Model Of Infantile Neuroaxonal Dystrophy

A F Geard(1) S Whaler(1) W Liu(1) G Massaro(1) M P Hughes(1) H R Nelvagal(1) L Poupon-Bejuit(1) S N Waddington(1,3) M A Kurian(1,2) A A Rahim(1)

1:UCL; 2:Great Ormond Street Hospital, London; 3:University of the Witwatersrand, South Africa

Introduction: Infantile neuroaxonal dystrophy (INAD) is a rare and lethal paediatric neurodegenerative disease. It is caused by biallelic mutations in the PLA2G6 gene, which codes for the enzyme calcium-independent phospholipase A2. Patients present with progressive neurological symptoms between six months and three years of age, with mortality typically occurring by 10 years old. No disease modifying treatments are available. 


Methods: We conducted an in-depth characterization of the pla2g6-inad knock-in mouse model. Following characterization, we investigated the therapeutic potential of an AAV9.hPLA2G6 vector administered intracerebroventricularly to neonatal and juvenile pla2g6-inad mice. We investigated survival, behavioural parameters, and histological analysis to assess therapeutic efficacy. 


Results: The average lifespan of the model is reduced to approximately 14 weeks, with weight loss and behavioural decline from 9 weeks old. Neuropathology studies showed neuronal loss and neuroinflammation in the brain and spinal cord, along with autophagic and lysosomal accumulation. A long term-study demonstrated that neonatally administered AAV9.hPLA2G6 gene therapy resulted in a significant improvement in all parameters measured including survival, weight, locomotor function, and neuronal counts in both the brain and spinal cord. Adult administrations to symptomatic mice have thus far shown increased survival of 21 weeks on average, improved behavioural function and ameliorated neurodegeneration.


Conclusion: This study provides novel insights into INAD disease pathology and cellular dysfunction in the CNS and suggests an AAV9-based therapy has potential to enable effective treatment of INAD. Further clinical translation studies are being undertaken with our industrial partner, Bloomsbury Genetic Therapies Ltd. 

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