Targeting fetal hemoglobin expression to treat β hemoglobinopathies

ABSTRACT

Introduction

Sickle cell disease and β thalassemia are the principal β hemoglobinopathies. The complex pathophysiology of sickle cell disease is initiated by sickle hemoglobin polymerization. In β thalassemia, insufficient β-globin synthesis results in excessive free α globin, ineffective erythropoiesis, and severe anemia. Fetal hemoglobin (HbF) prevents sickle hemoglobin polymerization; in β thalassemia HbF compensates for the deficit of normal hemoglobin. When HbF constitutes about a third of total cell hemoglobin, the complications of sickle cell disease are nearly totally prevented. Similarly, sufficient HbF in β thalassemia diminishes or prevents ineffective erythropoiesis and hemolysis.

Areas covered

This article examines the pathophysiology of β hemoglobinopathies, the physiology of HbF, intracellular distribution, and the regulation of HbF expression. Inducing high levels of HbF by targeting its regulatory pathways pharmacologically or with cell-based therapeutics provides major clinical benefit and perhaps a ‘cure.’

Expert opinion

Erythrocytes must contain about 10 pg of HbF to ‘cure’ sickle cell disease. If HbF is the only hemoglobin present, much higher levels are needed to ‘cure’ β thalassemia. These levels of HbF can be obtained by different iterations of gene therapy. Small molecule drugs that can achieve even modest pancellular HbF concentrations are a major unmet need.

KEYWORDS:

• Hereditary persistence of fetal hemoglobin
• gamma-globin gene
• gene deletion
• globin
• gene expression
• BCL11A
• gene therapy

Article highlights

• HbF is the major modulator of the phenotype of β hemoglobinopathies.

• Hydroxyurea is the standard of care for patients with the HbS-only phenotype of sickle cell disease because of its ability to induce increased levels of HbF.

• Autologous transplantation of HSPCs engineered to contain a HbF-like gene or that are engineered to repress BCL11A, the major repressor of HbF, increases HbF sufficiently for a functional cure of β hemoglobinopathies.

• Long-term benefits and potential toxicities of HbF-induced gene therapy remain to be determined.

• Given the complexities of current gene therapies, an orally available drug that achieves even modest levels of pancellular HbF expression has a much greater likelihood of improving the health of populations with β hemoglobinopathies.

List of Abbreviations

ATAC-seq:	=	Assay for Transposase-Accessible Chromatin sequencing
CHD4:	=	Chromodomain helicase DNA binding protein 4
DNMT1:	=	DNA methyltransferase 1
EED:	=	Embryonic ectodermal development
F-cells:	=	Erythrocytes with FACS-detectable HbF
FACS:	=	Fluorescent activated cell sorting
HbC:	=	hemoglobin C
HbF:	=	fetal hemoglobin
HbS:	=	sickle hemoglobin
HRI:	=	Heme regulated inhibitor
HPSCs:	=	hematopoietic stem and progenitor cells
HPLC:	=	high performance liquid chromatography
HU:	=	Hydroxyurea
HS:	=	Hypersensitive site
LDH:	=	Lactic dehydrogenase
LCR:	=	Locus control region
LSD1:	=	Lysine-specific demethylase-1
NO:	=	Nitric oxide
NonO:	=	Non-POU domain-containing octamer-binding protein
NuRD:	=	Nucleosome remodeling and histone deacetylase;
PRC2:	=	Polycomb repressive complex 2
RNA-seq:	=	RNA sequencing
ZNF410:	=	Zinc finger protein 410

Declaration of interest

The author is a consultant for, and serves on the Advisory Boards for Vertex Pharmaceuticals, Fulcrum Therapeutic; Data Monitoring Committee and Imara Inc.

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Funding

This paper was not funded.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose