1031 - Reactivation of fetal hemoglobin for therapy: From GWAS to the clinic

Abstract

The major hemoglobin disorders, b-thalassemia and sickle cell disease (SCD), are among the most common severe Mendelian disorders worldwide. Although the molecular bases of these diseases have been known for decades, treatment has been largely supportive, except for curative bone marrow transplantation. Classical family and genetic studies long ago established the beneficial impact of elevated fetal hemoglobin on the clinical phenotypes, and stimulated investigation into approaches for reactivation of silenced fetal hemoglobin as a therapeutic strategy. Despite elucidation of the principal regulators of erythroid gene transcription more than 2 decades ago, the basis for repression of fetal hemoglobin (HbF) during late gestation and after birth was elusive. Genome-wide association studies of HbF levels in 2007/8 revealed candidate loci, including the zinc-finger transcription factor BCL11A. Subsequently, combined surrogate genetics in cells, human genetics, and CRISPR/Cas9 saturating mutagenesis have established BCL11A as a principal repressor of HbF expression and identified discrete DNA sequences within an intragenic erythroid enhancer that are favorable for gene editing therapy. Through unbiased screening of potential BCL11A binding sequences we recently identified a novel recognition motif present in embryonic and fetal, but not adult, globin genes and showed that this site is mutated in rare individuals with classical hereditary persistence of hemoglobin, an entitly described 3 decades ago. Translation of basic findings to the clinic, through genetic or pharmacological means, is under intense investigation. Summary of the current state of these efforts will be discussed. Studies of BCL11A have greatly advanced a mechanistic understanding of the switch from fetal to adult hemoglobin, and illustrate the power of integrative genetic, biochemical, and hematologic approaches in providing opportunities for transformative management of the major hemoglobin disorders.