First-in-human high dose AAV9 intrathecal gene therapy for paediatric CLN7 disease: a phase 1, open-label, single ascending dose, non-randomised clinical trial.

Abstract

Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a paediatric lysosomal storage disease caused by mutations of the MFSD8 gene. Affected children have normal early development, but then suffer from progressive cognitive, motor, verbal, and visual decline. Ataxia and myoclonic epilepsy are predominant features of the condition, and there are no effective therapies. Death usually occurs by approximately age 11 years. While adeno-associated virus serotype 9 (AAV9) based gene therapy holds promise for treating monogenetic neurologic disorders, the impact of this intervention is limited by the maximum safe tolerable dose and the host immune response to the capsid and gene product. This study sought to confirm the safety of high dose intrathecal AAV-based gene therapy under a comprehensive immunosuppression regimen. This was a two-year open label, dose escalation, phase 1 first-in-human study of AAV9-based intrathecal gene therapy for CLN7. 4 participants (1 low dose, 3 high dose) were followed at regular intervals with blood work, CSF analysis, EEG, MRI, and measures of neurologic and neuropsychological function. This study provided evidence of safety for high dose intrathecal AAV9 based gene therapy in CLN7 disease under a specific immunosuppression regimen. Additionally, this study provides preliminary evidence of efficacy for this gene therapy. High dose intrathecal AAV based gene therapy can be pursued with adequate immunosuppression and monitoring for immune responses to the gene product. Additional long-term monitoring of the immune system during tapering of immunosuppression is needed to identify potential reactions to the gene product. This study was funded by The Batten's Hope Foundation, Mila's Miracle Foundation, Children's Health Dallas and Philanthropic Gifts to UT Southwestern. In addition, Emily R. Nettesheim received funding from NIH training grant 5T32GM131945-03 and Hamza Dahshi was supported in part by NIH award T32 GM152319.