Hematopoietic Stem Cell Gene Therapy for treatment of Ataxia telangiectasia (A-T)

• Applicant: Professorin Dr. Ute Modlich, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428639696

Ataxia telangiectasia (A-T) is a monogenetic, autosomal recessive disorder caused by inactivating mutations in the ATM gene. To date no curative therapy for A-T is available. For genetic disorders like A-T, curation by any other way than gene therapy is unfathomable and we propose to explore this possibility. With gene therapy, a healthy ATM gene copy could be added, or ATM mutations may be corrected. In the context of gene delivery to the hematopoietic system, retroviral/lentiviral gene transfer to hematopoietic stem cells (HSC) and their subsequent transplantation has demonstrated its potential for the treatment of several primary immune deficiencies and genome instability syndromes. By using gene editing, it is now possible to correct the underlying mutation in the gene and with this treating the cause of the hematopoietic disorder. As A-T displays a DNA repair defect, genomic modification in ATM-deficient cells may induce critical DNA damage leading to cell death or inducing malignant transformation and, therefore, gene therapy in this disorder appears especially challenging. Aim of this project is the development of a gene therapy approach to treat A-T. The gene transfer or correction will be performed in HSC and by their subsequent transplantation primarily correct the immunodeficiency. We will follow two different arms: (1) Gene transfer of the ATM cDNA using foamy viral vectors. As the ATM gene has a long coding sequence, we want to explore the use of foamy viral vectors that can transfer large transgenes. Even though not as well studied as lentiviral vectors, foamy viral vector transduction and transplantation of HSC has been demonstrated. (2) Gene correction of the A-T mutation by gene editing. The first approaches will be developed based on the Atm-deficient mouse model, but may be translated into human cells at later time points. Gene editing strategies will be developed in human cells.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Cooperation Partner: Professorin Dr. Janine Reichenbach