CRISPR Cas9 mediated gene therapy in Inherited Bone Marrow Failure Syndromes

Nadeesha Jayamini Samarasinghe Munugoda HewaRajendra KCAlex W HewittKirsten A Fairfax^*

• University of Tasmania College of Health and Medicine, Hobart, Australia

This systematic review evaluates CRISPR Cas9-mediated gene therapy for inherited bone marrow failure syndromes, a heterogenous group of rare inherited disorders marked by cytopenia, cancer predisposition, and multi organ involvement for which supportive care and allogenic haematopoietic stem cell transplantation provide cures for some, but remain imperfect, donor-limited and morbidity-prone. The objective of this review is to evaluate the current state of CRISPR Cas9-mediated gene therapy in inherited bone marrow failure syndromes with a focus on how this technology has been applied in experimental models and to correct pathogenic mutations, restoring haematopoietic function. We searched across three platforms, PubMed, Scopus, and Google Scholar for studies with combined inherited bone marrow failure syndromes with gene editing, prime editing, base editing or CRISPR Cas9. Of 876 records screened, 18 met inclusion criteria. Fanconi anaemia predominated (n=8) with additional work on Severe Congenital Neutropenia (n=3), Shwachman-Diamond syndrome (n=2), Diamond Blackfan syndrome (n=2), and single studies in Dyskeratosis Congenita, Congenital Amegakaryocytic Thrombocytopenia and MDS/AML predisposition. Overall, CRISPR Cas9 has demonstrated feasibility for ex vivo correction in inherited bone marrow failure syndromes, however, future clinical adaptation will depend on overcoming key hurdles, such as careful assessment of off-target effects, and regulatory approval for access for patients with rare disease to bridge the gap between preclinical and therapeutic application.