Basic Science and Pathogenesis.

Background: Frontotemporal dementia (FTD) presents with a change in personality, behaviour and language and is the second most common cause of young-onset dementia after Alzheimer's disease. Loss of function mutations in GRN, encoding progranulin (PGRN), causes FTD in the heterozygous state, accounting for 5-10% of all FTD cases. PGRN is essential for normal lysosomal function and neuronal survival. The PGRN reduction observed in FTD-GRN patients leads to lysosomal dysfunction, associated with the mis-accumulation of neuronal TDP-43 and exaggerated microglial reactivity that accelerates neurodegeneration. FTD-GRN represents a serious condition with significant unmet needs. AVB-101 is being developed as a one-time treatment for FTD-GRN administered bilaterally into the thalamus (ITM) by convection-enhanced delivery using a stereotaxic neurosurgical procedure.

Methods: AVB-101, a recombinant AAV9 vector, was designed to minimise vector dose and to restrict PGRN expression to neurons by engineering a cassette that includes (i) a codon-optimised GRN sequence, (ii) PGRN expression enhancers and (iii) a neuron-specific promoter. In vitro experimental testing of the construct was initially conducted in neuronal cultures. Efficacy studies were conducted in Grn knockout mice. Biodistribution studies were conducted first in sheep to optimize the route of administration and extended to non-human primates (NHPs) to assess the safety and tolerability of AVB-101.

Results: AVB-101 induces robust levels of PGRN expression in neurons when tested in vitro. In vivo, AVB-101: (a) can suppress neuronal lipofuscinosis even at the lowest dose tested in Grn null mice; (b) in sheep resulted in dose-dependent and widespread cortical and basal ganglia PGRN expression even at doses lower than commonly used with direct cerebrospinal fluid delivery modalities; (c) results in no expression of PGRN outside the CNS regardless of the animal model used; (d) in NHPs was well tolerated, with no mortality or clinically evident adverse effects; (e) in sheep and NHP drives PGRN expression to human-equivalent physiological levels in the temporal and frontal lobes, which are the cortical regions most severely affected in FTD-GRN.

Conclusions: The preclinical data suggest that intrathalamic infusion of AVB-101 constitutes a novel and promising approach to supplement PGRN in the CNS, supporting the clinical development of AVB-101 for FTD-GRN.