Molecular Medicine: Found in Translation

Abstract

Studies of the major hemoglobin disorders b-thalassemia and sickle cell disease (SCD) have laid a foundation for molecular medicine. While enormous progress has been made in understanding gene structure and regulation, translating molecular insights to therapy for the many individuals affected with these disorders has been challenging. Advances in three activities have recently converged to bring novel genetic and potentially curative treatments to clinical trials. First, improved lentiviral vectors for gene transfer into hematopoietic stem cells have revived somatic gene therapy for blood disorders. Second, elucidation of regulatory factors and mechanisms that control the normal developmental switch from fetal to adult hemoglobin has provided a route to the reactivation of the fetal form for therapy. Third, revolutionary methods of gene engineering permit molecular insights to be leveraged for patients. This perspective reviews how the promise of molecular medicine to bring transformative treatments to the clinical arena is finally being realized.

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

“…Increased expression of HbF lessens the severity of the b-hemoglobin disorders, sickle cell disease (SCD), and b-thalassemia. Reversing HbF silencing in adult cells has been at the forefront of efforts to treat b-hemoglobinopathies (Orkin, 2021).…”

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

“…The controls of the switching process are partly understood and depend largely on the activation of HbF repressors like the gene BCL11A. [5][6][7] The successes of gene therapy of β hemoglobinopathies 2,3 have prompted the question: can blood with high concentrations of HbF cause physiological impairment? HbF evolved to potentiate the transfer of O 2 from maternal blood to fetal tissues: a goal achieved by the higher O 2 affinity of HbF compared with HbA because of the insensitivity of HbF to 2,3 BPG, the major modulator of hemoglobin-O 2 affinity.…”

A cell-permeant nanobody-based degrader that induces fetal hemoglobin

“…Reactivation of fetal hemoglobin (HbF, α 2 γ 2 ) is a promising strategy to ameliorate clinical severity in patients with hemoglobin disorders ( 21 ). Patients with SCD that produce elevated HbF exhibit significantly improved survival rates ( 22 ).…”