Therapeutic use of CRISPR/Cas9 base editing for the treatment of Vanishing White Matter Disease
Leukodystrophies, such as Vanishing White Matter disease, are rare terminal brain disorders caused by the progressive loss of myelin in the central and peripheral nervous system. Since specific point mutations in the genes encoding the five subunits of the eukaryotic translation initiation factor 2B (Eif2B1-5) have been associated with onset and progression of myelin degeneration in VWMD, in vivo CRISPR/Cas9-base editing constitutes a promising treatment approach to revert these disease-causing mutations. Nevertheless, in vivo genome editing in patients still faces several challenges, including immunogenicity of delivery vehicles and Cas proteins and generation of off-target mutations that could induce malignant transformations.
The proposed project aims to tackle several of the aforementioned challenges in order to establish base editing for the treatment of VWMD. Using a series of read-outs ranging from genomics, transcriptomics, proteomics to behavioural analyses, we will evaluate the therapeutic efficacy and long-term effects of a CRISPR/Cas9-base editing treatment in vivo in a VWMD mouse model. As there are currently no curative therapies for VWMD and various other genetic brain disorders, such as Rett Syndrome, Huntington’s disease and Niemann-Pick disease, the here-developed approach of base editing and targeted viral delivery holds immense potential for future therapeutic applications, also beyond leukodystrophies.
Publications
Schmidheini L, Mathis N, Marquart KF, Rothgangl T, Kissling L, Böck D, Chanez C, Wang JP, Jinek M, Schwank G. Continuous directed evolution of a compact CjCas9 variant with broad PAM compatibility. Nat Chem Biol. 2024 Mar;20(3):333-343. doi: 10.1038/s41589-023-01427-x. Epub 2023 Sep 21. PMID: 37735239; PMCID: PMC7616171.
Weber Y, Böck D, Ivașcu A, Mathis N, Rothgangl T, Ioannidi EI, Blaudt AC, Tidecks L, Vadovics M, Muramatsu H, Reichmuth A, Marquart KF, Kissling L, Pardi N, Jinek M, Schwank G. Enhancing prime editor activity by directed protein evolution in yeast. Nat Commun. 2024 Mar 7;15(1):2092. doi: 10.1038/s41467-024-46107-z. PMID: 38453904; PMCID: PMC10920827.
Böck D, Wilhelm M, Mumenthaler J, Carpanese DF, Kulcsár PI, d'Aquin S, Cremonesi A, Rassi A, Häberle J, Patriarchi T, Schwank G. Base editing of Ptbp1 in neurons alleviates symptoms in a mouse model of Parkinson's disease. Elife. 2024 Dec 23;13:RP97180. doi: 10.7554/eLife.97180. PMID: 39714464; PMCID: PMC11666242.
Rothgangl T, Tálas A, Ioannidi EI, Weber Y, Böck D, Matsushita M, Villiger EA, Schmidheini L, Moon WJ, Lin PJC, Fan SHY, Marquart KF, Schwerdel C, Rimann N, Faccin E, Villiger L, Muramatsu H, Vadovics M, Cremonesi A, Kulcsár PI, Thöny B, Kopf M, Häberle J, Pardi N, Tam YK, Schwank G. Treatment of a metabolic liver disease in mice with a transient prime editing approach. Nat Biomed Eng. 2025 Oct;9(10):1705-1718. doi: 10.1038/s41551-025-01399-4. Epub 2025 May 20. PMID: 40394220; PMCID: PMC12532708.
Böck D, Tidecks L, Wilhelm M, ElGrawani W, Duss S, Trevisan C, Vena D, Reuss AM, Kissling L, Ranucci M, Privitera M, Polzer LK, Economides AE, Ioannidi EI, Mendes R, Weber Y, Leonardi J, Mumenthaler J, Villiger E, Goutagny R, Mathis C, Schmidheini L, Rothgangl T, Janjuha S, Patriarchi T, Bohacek J, Sych Y, Aguzzi A, Winterer J, Kompotis K, Schwank G. Prime editing of the β1 adrenoceptor in the brain restores physiological REM sleep in a mouse model of Alzheimer's disease. Nat Commun. 2025 Dec 9;16(1):10973. doi: 10.1038/s41467-025-65964-w. PMID: 41365977; PMCID: PMC12689628.