Gene Therapy and Genome Editing Treatment for Monogenetic Diseases大森 司1) Kashiwakura Y, Nakajima Y, Horinaka K, et al. Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy. bioRxiv. 2024. dio:10.1101/2024.12.05.626963.2) Baatartsogt N, Kashiwakura Y, Hiramoto T, et al. Universal base editing for hemophilia B. bioRxiv. 2024. dio:10.1101/2024.11.13.623331.3) Togashi T, Baatartsogt N, Nagao Y, et al. Cure of congenital purpura fulminans via expression of engineered protein C through neonatal genome editing in mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2024. 44(12):2616-2627. 4) Hiramoto T, Inaba H, Baatartsogt N, et al. Genome editing of patient-derived iPSCs identifies a deep intronic variant causing aberrant splicing in hemophilia A. Blood Advances. 2023. 7(22):017-7027.5) Hino T, Omura SN, Nakagawa R, et al. An AsCas12f-based compact genome editing tool derived by deep mutational scanning and structural analysis. Cell. 2023. 186(22):4920-4935.自治医科大学 医学部生化学講座 病態生化学部門自治医科大学 遺伝子治療研究センター10. 遺伝性疾患に対する in vivo 遺伝子治療・ゲノム編集治療Gene therapy and genome editing are gaining attention as next-generation treatments for intractable diseases. Adeno-associated virus (AAV) vectors are the most used modality for in vivo gene transfer to the liver, and several AAV vector-mediated gene therapy drugs have already been approved. Current gene therapy primarily involves the delivery of functional genes into cells, essentially serving as a form of gene supplementation therapy. In contrast, genome editing directly targets the chromosomal DNA, with the expectation that the effects will be permanent once a cell undergoes editing. The discovery of CRISPR-Cas9 has made genome editing therapy a practical reality. Recent trials have demonstrated successful liver genome editing using lipid nanoparticles to deliver Cas9 mRNA and sgRNA, knocking out the TTR gene in patients with transthyretin amyloidosis. In β-hemoglobinopathies, knocking out the BCL11A gene in hematopoietic stem cells restored fetal hemoglobin, improving anemia. Furthermore, techniques like base editing and prime editing, which can rewrite pathological variants, are advancing rapidly and are already being applied in human clinical trials. Here, I will provide an overview of the recent remarkable advancements in gene therapy and genome editing treatments, along with data from our own research on gene therapy and genome editing for monogenic diseases.Tsukasa OhmoriDepartment of Biochemistry, Jichi Medical University School of MedicineCenter for Gene Therapy Research, Jichi Medical University21
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