Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates

Abstract

Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90–94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0451-7) contains supplementary material, which is available to authorized users.

Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS

“…These findings highlight the potential clinical utility of heparan binding-deficient AAV2 vectors and have important implications for the treatment of neurological diseases requiring widespread and global distribution of gene therapy in the brain and spinal cord, such as motor neuron diseases and lysosomal storage disorders. Others have reported oligodendrocyte transduction in subcortical areas, 25 but this is the first demonstration of oligodendrocyte transduction in the NHP cortex by a modified AAV2 capsid. AAV2-HBKO has possible application for demyelinating diseases, leukodystrophies, and other myelin disorders.…”

T cell infiltration in both human multiple system atrophy and a novel mouse model of the disease

“…More detailed information of the development, construction, purification, and quality control of the Olig001 AAVs are described elsewhere [37,43]. Briefly, the AAV-Olig001 vectors which have a high tropism for oligodendrocytes are packaged with a self-complementary genome with transgene expression mediated by the CBh promoter and bovine growth hormone polyA [24].…”

Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner

“…Expression of oligodendroglial α-synuclein has been generated following intrastriatal injection of chimeric viral vectors expressing α-synuclein under the control of MBP; interestingly, phosphorylated and proteinase-resistant α-synuclein is detected in the striatum and substantia nigra, indicating, in addition, the capacity for seeding (Bassil et al, 2017). Other viral vector models are currently assessed in rodent and nonhuman primates (Mandel et al, 2017).…”