Abstract: The present disclosure provides methods and compositions for genetically modifying hematopoietic stem and progenitor cells (HSPCs), in particular by replacing the HBB locus in the HSPCs with a transgene encoding alpha globin.

Abstract: Therapeutic methods and compositions for the in utero or postnatal treatment of diseases associated with alternative splicing are provided. Compositions of the disclosure include delivery nanoparticles with an inner region surrounded by a nucleic acid scaffolding that is, in turn, linked to therapeutic agents that promote healthy mRNA splicing phenotypes in fetal cells when the compositions are delivered to a fetus in utero or in a patient after birth.

Abstract: The disclosure provide methods and compositions that use gene editing or gene therapy to treat alpha thalassemia major. The gene editing may be performed ex vivo in fetal cells or cells obtained after birth to improve production of globin, with those cells then delivered to the fetus. In other embodiments, gene editing reagents are delivered to the fetus or the patient after birth in vivo to edit genes of the alpha-globin cluster and improve globin production. Gene editing system such as CRISPR, TALENs, or ZFNs are used to increase production of alpha, zeta, or theta globin and/or to decrease production of gamma globin. Globin production may be improved by inserting a copy of globin gene or mutating a globin gene to change its expression. Any of the gene editing strategies may be performed in conjunction with delivering to a fetus or patient after birth a therapeutic blood transfusion. Exemplary patients after birth are patients no older than one year of age.