Intrathalamic delivery of adeno-associated viral vector expressing progranulin as gene therapy for GRN-related frontotemporal dementia.

GRN mutations leading to progranulin haploinsufficiency can cause frontotemporal dementia. AVB-101, an investigational gene therapy comprising an adeno-associated virus construct expressing codon-optimized human GRN under a neuronal promoter, was delivered intrathalamically to mice, sheep, and non-human primates. AVB-101 reversed pathology in Grn -/- mice and achieved widespread cortical biodistribution in sheep brain, with human progranulin protein detected in the majority of prefrontal cortical neurons. Conversely, human progranulin was undetectable in sheep cortical neurons following intra-cisterna magna administration of AVB-101 or adeno-associated viruses containing progranulin under a ubiquitous promoter. AVB-101 was well tolerated in cynomolgus macaques with no adverse events reported for the 6-month duration of the study. At all doses tested, human progranulin protein was detected throughout the cortex while absent in peripheral tissues. Human progranulin levels in cerebrospinal fluid and prefrontal cortex tissue were closely correlated in sheep and non-human primates, confirming that an increase in cerebrospinal fluid progranulin levels reflects neuronal expression of AVB-101. Thus, AVB-101 is well tolerated in various animal models, and intrathalamic administration delivers progranulin at levels sufficient for cross-correction throughout the brain. These data support the progression of AVB-101 to clinical development in humans with frontotemporal dementia caused by GRN mutations.