Talk Abstracts

Talk on Tuesday 09:15-09:30am submitted by Jessica Herstine

AAV-mediated gene supplementation provides thorough correction in two models of vanishing white matter disease

Jessica A. Herstine (Molecular, Cellular, and Developmental Biology Graduate Program), Tamara J. Stevenson, Pi-Kai Chang, Julia Wentz, Erika Scholl (Department of Pediatrics, University of Utah, Salt Lake City, UT ), Sergiy Chornyy, Jessica Rediger, Nettie Pyne, Tatyana Vetter (Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, Columbus, OH), Kevin M. Flanigan (Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, Columbus, OH), Joshua Bonkowsky (Department of Pediatrics, University of Utah, Salt Lake City, UT ), Allison Bradbury (Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Childrens Hospital, Columbus, OH)

Abstract:
Vanishing White Matter Disease (VWM) is a childhood leukodystrophy that leads to premature death.^1,2 There are no treatments. Caused by autosomal recessive, loss of function mutations in the subunits of eukaryotic initiation factor 2B (eIF2B), VWM most commonly originates from pathologic variants in EIF2B5.³ Due to VWM’s monogenic nature, it is a promising candidate for adeno-associated virus (AAV)-mediated gene supplementation therapy. Prior VWM studies revealed that astrocytes are a critical target for therapy, as their differentiation, morphology, and function are impaired, thus mediating disease progression.^4,5 To serve as a baseline for correction, we first aimed to characterize the newly identified and severe VWM Eif2b5^I98M murine model. We found that these mice display significant loss of mobility, ataxic gait, and demyelination all within a shortened lifespan (5.5 months). The integrated stress response—a molecular pathway regulated by eIF2B that rescues homeostasis during cellular stress—is dysregulated, thereby supporting that these mice are displaying classic VWM phenotypes. To provide targeted disease correction, we designed gene replacement constructs to drive therapeutic EIF2B5 transgene expression in astrocytes. Thus, we are currently evaluating three astrocyte-specific and one ubiquitous therapeutic AAV vectors in two murine VWM models, R191H and I98M, and are monitoring disease progression. Our data suggests that gene therapy delays disease onset, partially rescues motor function, and attenuates myelin loss in both models. Treated I98M mice also have significantly extended lifespans, with our longest extension of life exceeding 1 year. Overall, we anticipate the development of a lead astrocyte-targeted gene therapy in which the data will be strengthened through clinically relevant assessments of two VWM murine models, allowing for expeditious translation to the clinic.

References:
1. Van Der Knaap, M. S. et al. A new leukoencephalopathy with vanishing white matter. Neurology 48, 845–855 (1997).
2. Hamilton, E. M. C. et al. Natural History of Vanishing White Matter. Ann. Neurol. 84, 274–288 (2018).
3. Fogli, A. et al. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 62, 1509–1517 (2004).
4. Bugiani, M., Vuong, C., Breur, M. & van der Knaap, M. S. Vanishing white matter: a leukodystrophy due to astrocytic dysfunction. Brain Pathol. 28, 408–421 (2018).
5. Dooves, S. et al. Astrocytes are central in the pathomechanisms of vanishing white matter. J. Clin. Invest. 126, 1512–1524 (2016).

Keywords: Leukodystrophy , Astrocytes, Gene Therapy