Provided are compositions and methods for the treatment of hemoglobinopathies such as thalassemias and sickle cell disease. Compositions and methods include one or more endonuclease(s) or endonuclease fusion protein(s), including one or more homing endonuclease(s) and/or homing endonuclease fusion protein(s) and/or CRISPR endonuclease(s) and/or CRISPR endonuclease fusion protein(s): (a) to disrupt a Bcl1 1a coding region； (b) to disrupt a Bcl1 1a gene regulatory region； (c) to modify an adult human ²-globin locus； (d) to disrupt a HbF silencing DNA regulatory element or pathway, such as a Bcl1 1a-regulated HbF silencing region； (e) to mutate one or more ³-globin gene promoter(s) to achieve increased expression of a ³-globin gene； (f) to mutate one or more ´-globin gene promoter(s) to achieve increased expression of a ´-globin gene； and/or (g) to correct one or more ²-globin gene mutation(s).
