Keiser, M. S. | Search bioRxiv

bioRxiv2024

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Huntingtons disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Additionally, for adeno-associated viruses (AAVs) intravascular delivery exposes peripheral tissues to the vast majority of the therapy, increasing the risk of immune responses and the quantity and associated cost of goods required for therapeutically relevant brain penetration levels. Here, we found that low dose, low volume delivery of unbiased AAV libraries into a focused brain region allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies at doses orders of magnitude lower than used in current clinical trials. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and also potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.

neuroscience↗

bioRxiv2023

APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Epidemiological studies show that individuals who carry the relatively uncommon APOE {varepsilon}2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE {varepsilon}4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE {varepsilon}2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE {varepsilon}2, or if APOE {varepsilon}2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established A{beta} plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk {varepsilon}4 allele. One Sentence SummaryIntroduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques.

neuroscience↗