TY - JOUR
T1 - In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice
AU - Böck, Desirée
AU - Revers, Ilma M.
AU - Bomhof, Anastasia S. J.
AU - Hillen, Anne E. J.
AU - Boeijink, Claire
AU - Kissling, Lucas
AU - Egli, Sabina
AU - Moreno-Mateos, Miguel A.
AU - van der Knaap, Marjo S.
AU - van Til, Niek P.
AU - Schwank, Gerald
N1 - Publisher Copyright: © 2024 The American Society of Gene and Cell Therapy
PY - 2024
Y1 - 2024
N2 - Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base-editing approaches for the treatment of VWM or other leukodystrophies.
AB - Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base-editing approaches for the treatment of VWM or other leukodystrophies.
KW - CRISPR-Cas genome editing
KW - adenine base editing
KW - adeno-associated viral vectors
KW - central nervous system
KW - disease treatment‘
KW - gene therapy
KW - genetic brain disorders
KW - leukodystrophies
KW - next-generation sequencing
KW - vanishing white matter
UR - http://www.scopus.com/inward/record.url?scp=85188542608&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2024.03.009
DO - 10.1016/j.ymthe.2024.03.009
M3 - Article
C2 - 38454603
SN - 1525-0016
JO - Molecular therapy
JF - Molecular therapy
ER -