Using the V127 prion variant for prion disease gene therapy: A hypothesis

Abstract

Prion diseases are fatal neurodegenerative disorders caused by abnormal folding of prion proteins. Prion diseases can be sporadic, genetic, or acquired. In Papua New Guinea, the Fore people were afflicted by an acquired prion disease, kuru, caused by the consumption of prion-infected brain tissue. Owing to the strong selective pressure of this community-wide disease, many Fore people are heterozygous for the G127V prion variant that confers kuru resistance. Animal models demonstrated that mice heterozygous for the variant prion are resistant to both kuru and classical CJD but can still be infected with variant CJD. However, mice homozygous for the V127 variant form are resistant to all forms of prion infection, and further data demonstrate that this variant suppresses prion disease in a dose-dependent manner. Advances have been made in gene therapy for the central nervous system. The hypothesis proposed is that exogenous overexpression of the V127 prion variant in the brains of prion disease patients and potential patients interferes with the propagation of misfolded prion protein molecules, thereby arresting disease progression and possibly preventing initiation. Therefore, this V127 approach could be therapeutic for prion disease and preventive for individuals with genetic prion disease mutations. Hence, this paper proposes gene therapy for prion disease via the overexpression of the V127 variant in patient brain cells. The objectives of this approach would be to delay and/or reduce disease progression, to possibly be curative for sporadic and acquired prion disease, and as a preventive measure against genetic prion disease.