Diamond Blackfan anemia (DBA) is a bone marrow failure syndrome (BMFS) with an estimated prevalence of 7 cases per million life births showing incidence and distribution of patients across different countries (L Da Costa, Leblanc, and Mohandas 2020). The hallmark of DBA is macrocytic anemia, which is typically presented at the first year, and frequently evolve to neutropenia and thrombocytopenia, and in some cases to a myelodisplac syndrome or acute myeloid leukemia (Ruggero and Shimamura 2014).
Mutations in 20 DBA genes, plus 4 “DBA–like” genes account for 70-80% of DBA (L Da Costa, Leblanc, and Mohandas 2020). Most of mutations (>90%) have been identified to occur in only 6 of those ribosomal protein (RP) genes: RPS19 (25%-30%), RPL5 (7%-12%), RPS26 (6.6%-9%), RPL11 (5%-7%), RPL35A (2%-3%) and RPS24 (2.4%-3%) (Lydie Da Costa et al. 2020). DBA patients are typically haplo-insufficient for the RP gene (one gene unaffected, the other inactivated) leading to a substantial reduced production of functional ribosomes.
To date, allogenic hematopoietic stem cell transplantation (allo-HSCT) is the only available curative treatment for DBA patients. Only a minority of patients have access to a suitable donor and furthermore, the clinical outcome of DBA patients transplanted with alternative donors after the age of 10 is very poor. Consequently, new advanced therapies able to restore the clinical signs of DBA and improve the quality of life from patients with this disease, are therefore on demand.
Based onthe expertise of our team in preclinical traslational studies in gene therapy we are developing different non-targeted and targeted gene therapy aproaches to restore the hematopoietic clinical signs of DBA patients. Recently the preclinical resulst obtained in the lentiviral mediated gene therapy aproach to treat RPS19-haploinsuficiency in DBA patintes have allowed the designation of this strategy as an orphan medicinal product for the treatment of Diamond-Blackfan anemia by the European Medicaments Agency (EMA/OD/0000060407). Proof of concept in other genes more tightly regulated are also on going more specific with targeted approaches using gene editing strategies.
