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A self-complementary recombinant adeno-associated virus vector coding for an anchorless prion protein carrying the G127V mutation extends survival in a rodent prion disease model

ABSTRACT: The replacement of a single codon in the human prion gene, causing the substitution of glycine with valine at position 127 (G127V) of the prion protein (PrP), prevents development of prion disease. We set out to explore if prion disease survival extension manifests in mice if the V127 mutant is delivered through a recombinant adeno-associated virus (rAAV) packaged as a self-complementary DNA. The notorious delivery limitations of rAAVs were overcome using a cross-correction approach that relied on the expression of the mutation in the context of glycosylphosphatidylinositoI-anchorless (ΔGPI) PrP. In this proof-of-concept study, we inoculated Rocky Mountain Laboratory (RML) prions into knock-in mice, in which the endogenous murine prion protein gene (Prnp) was replaced with the bank vole prion protein gene (BvPrnp). Prion-inoculated mice that were retro-orbitally transduced with a protective rAAV vector encoding BvPrnpV127ΔGPI survived ~50 days longer than control mice that were unprotected. A deep proteomic analysis revealed that BvPrnpV127ΔGPI was protective by slowing perturbations to the proteome observed in late-stage RML prion disease. In addition to capturing details of synaptic decay and depletion of proteins in proximity to PrP, the proteomic dataset revealed the identity of proteins of potential diagnostic value that may be central to the brain’s attempt to fight prion disease by contributing to astrocytosis or microgliosis, by coping with calcium influx, or by enhancing the endoplasmic reticulum processing of essential proteins. Taken together, our results demonstrate that a gene therapy based on a GPI-anchorless PrP containing the G127V mutation can delay the onset of prion disease in mice, providing a framework for development of a corresponding therapy in humans.

INSTRUMENT(S):

ORGANISM(S): Prion Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: cunjie zhang

LAB HEAD: Gerold Schmitt-Ulms

PROVIDER: PXD076487 | Pride | 2026-07-28

REPOSITORIES: Pride

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			Action	DRS
	OA03_BvPrnp_9P31_67_ES900_200ng.raw	Raw
	OA03_BvPrnp_9P31_69_ES900_200ng.raw	Raw
	OA03_BvPrnp_F_ES900_200ng.raw	Raw
	OA03_BvPrnp_G127V_80_ES900_200ng.raw	Raw
	OA03_BvPrnp_G127V_87_ES900_200ng_1.raw	Raw

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Project description:Background: APOE polymorphism affects the risk of occurrence and the rate of progression in several neurodegenerative diseases including late-onset Alzheimer’s disease, primary tauopathies, α-synucleinopathy, and age-related macular degeneration, but its role in prion pathogenesis remains unestablished. Using APOE targeted replacement (TR) mice, we investigated how APOE genotype affects key neurodegenerative mechanisms involved in prion pathology. Methods: Male and female ε2/ε2, ε3/ε3, and ε4/ε4 APOE-TR mice were inoculated with 22L mouse adapted scrapie strain or normal brain homogenate and followed using serial behavioral testing from 10-week post inoculation (wpi.) onward. Mice were euthanized at 23 wpi. when all prion-infected animals were visibly symptomatic. Multiple neuropathological, biochemical, and transcriptomic metrics were analyzed and compared across animals of different APOE genotypes. Results: ε4/ε422L mice featured the shortest disease latency time, the worst neurological score at the end of the study, and the highest load of spongiform lesions. ε2/ε222L mice performed significantly better compared to ε4/ε422L mice but also significantly worse than ε3/ε322L animals. Numerous aspects of PrP proteinopathy were exacerbated in the presence of the ε4 allele including increased PrPSc accumulation, reduced PrP solubility, and increased PrP oligomerization. These metrics were comparable between ε2/ε222L and ε3/ε322L mice. Prion pathology significantly increased brain apolipoprotein (apo) E levels, with the greatest increase in ε4/ε422L mice. All apoE isoforms formed complexes with conformationally altered PrP, but in ε4/ε422L mice the PrP/apoE interaction was the strongest. The load of reactive microglia and astrocytes, transcriptomic markers representative of neurodegenerative microglia and chronically reactive astrocytes were the highest in ε4/ε422L mice, but they also were significantly upregulated in ε2/ε222L mice compared to ε3/ε322L animals. Conclusions: APOE polymorphism differentially regulates the progression of prion pathology. We identified two mechanisms attributable to the detrimental effect endowed by the ε4 allele: the increased conversion and accumulation of the PrPSc conformer, and the worsening of prion-associated neuroinflammation. Although less severe than ε4, the ε2 allele also is associated with an increased inflammatory response, rendering disease outcome worse compared to the ε3 allele. Findings of this animal model study suggest both ε4 and ε2 alleles are disadvantageous determinants in prion pathology.

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A self-complementary recombinant adeno-associated virus vector coding for an anchorless prion protein carrying the G127V mutation extends survival in a rodent prion disease model

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