Year: 2021
Type: editorial
Abstract: Mutation-Specific Gene Editing for Blood DisordersHundreds of inherited blood disorders have been characterized and in their majority are still without effective treatments.Although many of them are, in principle, curable by allogeneic hematopoietic stem cell (HSC) transplantation, limited availability of compatible donors and persistent associated risks of treatment-related morbidity and mortality have prompted the search for alternative cures.As a result, gene therapy treatments have been developed, and for some of the more prominent blood disorders these have reached the clinic and even market approval.Presently, the most advanced approaches are based on ex vivo therapy by gene addition or genome editing, with the emerging prospect of in vivo therapies (Li et al., 2021a; 2021b), which would avoid myeloablation and associated risks of adverse events in the clinic (Frangoul et al., 2020; BioPharma Dive 2021).Permanent gene addition by semi-randomly integrating vectors poses the inherent risk of insertional mutagenesis and of host gene perturbation in HSCs, especially if promoter-proximal integration is favoured or if strong enhancer/promoter regions are included in the transgene cassette (Cattoglio et al. 2007;Servick, 2021).Therefore, the use of editing tools for gene correction, for targeted gene addition or for targeting of disease modifiers is the basis for an ever increasing number of upcoming therapies.Disruption of disease modifiers with gene editing tools as it is currently applied in clinical trials depends on the existence of therapeutically relevant modifiers for a given disease and requires a fundamental understanding of disease pathology, which for many blood disorders is still absent.In this context, mutation-specific editing would be solely based on knowledge of the underlying causative mutations and would represent the most direct curative approach for the majority of inherited defects.Such therapies targeting specific mutations often suffer from low efficiencies in HSCs, and the development costs can be disproportionate for the usually small number of patients that might benefit from the new therapy.To address these particular shortcomings of mutation-specific therapy and to enhance efficiency of treatments in general and thus to lower dosage requirements and risks to patients, therapy development for blood disorders needs novel strategies as much as it needs incremental improvements to existing protocols.In this respect, this Special Issue on Mutation-Specific Gene Editing for Blood Disorders covers an exceptional selection of contributions on mutation-specific gene editing in particular, and more generally on the development of associated concepts, protocols, technologies and corresponding regulatory and socio-economic conditions.The featured reviews and original articles offer expert perspectives on HSC-based therapies and particularly editing for hemoglobinopathies, on bone marrow failure syndromes and blood malignancies, on editing platforms, pathways and delivery methods, on targeted insertion of therapeutic transgenes and on the assessment of off-target activity of gene editing tools:
Source: Frontiers in Genome Editing
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,900
OpenAlex ID: W3202572809