1. Introduction
Sickle cell anemia (SCA) is the most common form of
sickle cell disease (SCD), a group of genetic disorders caused by
defective hemoglobin genes (1). SCA
is a prevalent hemoglobin anomaly worldwide and a major cause of
child mortality in West Africa, accounting for 9-16% of deaths
(2). It is caused by a point
mutation on chromosome 11, where valine replaces glutamic acid in
the β-globin chain, leading to hemoglobin S (HbS) formation. Under
low oxygen conditions, HbS polymerizes, reducing red blood cell
mobility, increasing fragility, and causing vaso-occlusive
complications and hemolysis (3).
Even though the molecular basis of SCA is well-known and the
pathophysiology of the disease is better understood, there has been
a substantial lag in its application to the development of safe and
effective therapies. Recent studies underscore the therapeutic
potential of reactivating fetal hemoglobin (HbF), which is mediated
by epigenetic processes. The present review discusses the
mechanisms through which targeting epigenetic regulators and
transcriptional repressors can increase HbF and alleviate SCA
pathology.
2. Importance of the γ-globin genes and HbF
in SCA
HbF, composed of two α- and two γ-globin chains
produced by the γ-globin genes, is dominant throughout fetal life,
but decreases postnatally due to hemoglobin switching (4). Adults have residual HbF levels
(usually 1%) (5). The γ-globin
genes (HBG1 and HBG2) are crucial in SCA pathophysiology, as an
increased expression of HbF reduces disease severity, improves red
blood cell lifespan and enhances erythropoiesis efficiency
(6). Individuals with the
hereditary persistence of HbF are often clinically asymptomatic
(7). Thus, re-inducing HbF through
γ-globin gene activation offers a promising therapeutic
strategy.
3. Epigenetic regulation of γ-globin gene
expression
Epigenetic mechanisms regulate gene expression
without altering the deoxyribonucleic acid (DNA) sequence and
include the following:
DNA methylation
The methylation of CpG islands in the γ-globin
promoter inhibits its expression (8). This suppression is carried out by DNA
methyltransferases (DNMTs). DNMT inhibitors can demethylate the
γ-globin promoter and restore HbF expression (9).
Histone modifications
The acetylation of lysine residues via histone
acetyltransferases (HATs) reduces histone-DNA interactions, making
chromatin more accessible to transcription factors and promoting
gene expression, whereas deacetylation via histone deacetylases
(HDACs) compacts chromatin and represses gene expression (10). Histone methylation by histone
methyltransferases (HMTs) or demethylation by lysine-specific
demethylase 1 (LSD1) also influences γ-globin transcription
(11). Protein arginine
methyltransferase 5 (PRMT5) and H3K27me3 are associated with
γ-globin silencing (12).
Adenosine-20,30-dialdehyde, a methyltransferase inhibitor, was
previously demonstrated to stimulate γ-globin gene expression in
human early-stage cultured red blood cell precursors, suggesting
that PRMT5 catalytic activity may be mechanically associated with
γ-globin gene suppression (13).
Transcriptionally active chromatin is associated with the
trimethylation of histone H3, specifically lysine at position 4
(H3K4me3), while H3K27me3 and H3K9Me3 result in tight chromatin,
which suppresses gene expression (14).
Transcription factors and chromatin
remodelers
B-cell lymphoma/leukemia 11A (BCL11A) and zinc
finger and BTB domain containing 7A (ZBTB7A) are key
transcriptional repressors of the γ-globin gene. To maintain a
suppressed chromatin state, they enlist the nucleosome remodeling
and deacetylase complex/chromodomain helicase DNA-binding protein 4
(NuRD/CHD4) (15). Other elements
that control these repressors and function as indirect targets for
HbF induction include zinc finger protein 410 (ZNF410) and
hypermethylated in cancer 2 (HIC2) (16). Furthermore, epigenetic control is
reversible and dynamic, rendering it a potential target for
therapeutic applications (17).
4. Current approaches targeting epigenetic
modifications to increase HbF production
Investigations into certain HDAC antagonists, such
as short-chain fatty acids, have demonstrated potential for
triggering the production of HbF (18). The clinical development of
phosphodiesterase 9 inhibitors (PF-04447943; ClinicalTrials.gov Identifier: NCT02114203-completed),
mechanistic target of rapamycin (mTOR) inhibitors, such as
sirolimus (Sirthalaclin trial; ClinicalTrials.gov Identifier: NCT03877809-completed;
mechanistic proof of HbF induction relevant to sickle cell
disease), and 3,4-dihydroxyphenylalanine DOPA decarboxylase
inhibitors such as benserazide (BENeFiTS trial; ClinicalTrials.gov Identifier: NCT04432623-ongoing)
has demonstrated enhanced γ-globin or HbF expression, although none
has established long-term transfusion independence in
hemoglobinopathies (19-21).
The molecular links between the alleged mechanisms of action of
these agents and epigenetic modifications that may influence HbF
production remain unclear. The selective erythroid deletion of
BCL11A in mice has shown promise in the treatment of SCA (22), leading to clinical studies using
genome modification with promising outcomes (23,24).
Single BCL11A or ZBTB7A knockout (KO) leads to
40-50% HbF expression in human erythroid progenitors, whereas dual
KO results in ~90-100% HbF, indicating their independent
contribution to repression. While adult-stage ZBTB7A deletion
causes moderate macrocytic anemia, complete knockout results in
embryonic mortality due to severe anemia (15). In hematopoietic stem and progenitor
cell (HSPC)-derived erythroblasts, ZBTB7A reduction also postpones
erythroid development. Future research is required to identify an
optimal therapeutic strategy where selectively inhibiting ZBTB7A in
adults induces HbF without adverse effects. Expanding upon the
fundamental knowledge of transcription factors linked to HbF
repression, the following paragraphs discuss other epigenetic
regulators that provide novel therapeutic options for the
reactivation of γ-globin expression.
Epigenetic regulators
ZNF410 is a transcription factor with a single known
target, CHD4, to stimulate the transcription of γ-globin
(HBG1/2) genes, rendering it a suitable target for HbF reactivation
(25). The deletion of ZNF410 does
not affect erythroid development, and leads to a marked increase in
the levels of HBG1/2, and a corresponding decrease in the level of
β-globin gene in various cell models and mice. Dual BCL11A and
ZNF410 knockdown enhances HbF production more effectively than
targeting BCL11A alone, rendering ZNF410 a promising therapeutic
target for SCD and β-thalassemia (26).
HIC2 is a zinc finger transcription factor that
plays a critical role in gene regulation and development. It
functions as a transcriptional repressor for BCL11A, thereby
promoting HbF production by reducing chromatin accessibility at
BCL11A enhancers (16).
Additionally, widely interspaced zinc finger (WIZ) degradation via
molecular glue degraders has been explored as a strategy to induce
HbF (27). OTQ923, a genome-edited
hematopoietic stem and progenitor cell product, was evaluated in a
first-in-patient phase I/II clinical study to decrease the
biological activity of BCL11A, boost HbF and decrease SCD-related
complications. However, that study was discontinued for commercial
reasons rather than safety concerns (ClinicalTrials.gov Identifier: NCT04443907). Presently
under investigation is a multi-center, open-label, non-randomized,
phase 2 research (GRASP, BMT CTN 2001) that targets BCL11A to raise
HbF in patients with SCD (ClinicalTrials.gov Identifier: NCT05353647).
5. Fetal hemoglobin boosters:
Pharmacological agents
Inhibitors of DNMT (such as decitabine), HDAC (such
as butyrate, vorinostat and givinostat), and LSD1 have been
demonstrated to increase HbF (28).
Hydroxyurea, however, not epigenetic in effect, remains a key
component of therapy due to its potential to produce HbF (29). Through DNA hypomethylation, DNMT
inhibitors, such as decitabine and 5-azacytidine can restore the
expression of γ-globin genes (30).
However, the clinical development of 5-azacytidine for
hemoglobinopathies was discontinued due to severe effects, although
the medication is still used for specific blood-related cancers
(31). The clinical success of
hydroxyurea is mostly owing to its ability to produce HbF, possibly
through epigenetic modifications (32).
Mechanisms of action of hydroxyurea as
an HbF inducer
In SCA, hydroxyurea raises HbF levels via two
distinct processes: i) Ribonucleotide reductase inhibition, which
encourages the selection of erythroid precursors with a high HbF
expression; and ii) the direct selection of HbF cell formation by
inhibition of soluble guanylate cyclase (28).
The most widely accepted theory is that it triggers
‘stress erythropoiesis’, which recruits primitive erythroid
precursors that have the capacity to produce HbF, resulting in
elevated HbF levels and a corresponding decrease in the proportion
of HbS (32). Hydroxyurea alters
methylation and demethylation processes at the γ-globin gene
promoter to boost γ-globin expression; however, these changes do
not significantly increase fetal globin reactivation (33). Another proposed mechanism involves
hydroxyurea-driven nitric oxide production, which increases
intracellular cyclic guanosine monophosphate-protein kinase G,
ultimately inducing HbF synthesis. However, the exact mechanisms
involved remain unknown.
HDAC 1/2 inhibitors in SCA:
Preclinical studies and therapeutic potential
HDAC1 and HDAC2 inhibitors have shown promise in the
treatment of SCA by inducing HbF production. Non-selective HDAC
inhibitors, such as butyrates, have been shown to be effective
(34). However, side-effects and
gene expression issues need to be addressed for long-term effective
treatments, including the selective suppression of HDAC-1 or
HDAC-2(35). The selective
inhibition of HDAC1 and HDAC2 inhibitors modifies the chromatin
structure of the β-globin gene, producing HbF without directly
affecting bone marrow (36). HDAC
inhibitors enhance histone acetylation, opening chromatin and
increasing γ-globin transcription.
According to Di Micco et al (37), HDAC-1 and HDAC-2 share 85% identity
and 93% similarity, rendering selective chemicals challenging.
However, they regulate gene expression for γ-globin induction,
eliminating the need for selectivity (37). Acetylon Pharmaceuticals, Inc.
developed ACY-957, a chemical with a zinc-chelating benzamide
group, that increases histone acetylation and GATA2 binding in
cells. It suppresses HDAC1/2 and enhances γ-globin mRNA expression
(38). The targeted inhibition of
HDAC1 and HDAC2 in adult human red blood cells increases HbF
production without altering the cell cycle (39). Romidepsin (40), the HDAC1/3 inhibitor, MS-275
(entinostat) (41), and givinostat,
a hydroxamate inhibitor, also promote γ-globin gene expression
without disrupting cell growth (42). The genetic knockdown of HDAC1/2
increases HbF levels, and combination therapy with hydroxyurea
enhances γ-globin synthesis (43).
This is further enhanced by MS-275(43). A phase 1 trial of panobinostat, a
pan-HDAC inhibitor, is currently underway in adult patients with
SCD (ClinicalTrials.gov identifier:
NCT01245179). CT-101, a class I HDAC inhibitor, has been reported
to selectively activate γ-globin transcription, leading to elevated
F-cells and HbF levels with minimal cytotoxicity. In combination
with hydroxyurea, it results in an even greater increase in HbF
levels.
These results highlight the potential of these
agents as pharmacological inducers of HbF. However, despite
promising preclinical findings, there is still a dearth of human
clinical proof (44). A summary of
the aforementioned pharmacologic HbF inducers, their mechanisms of
action and current clinical status is presented in Table I.
 | Table IPharmacological HbF inducers:
Mechanisms of action and clinical status. |
Table I
Pharmacological HbF inducers:
Mechanisms of action and clinical status.
| Agent/class | Proposed
mechanism(s) | Clinical
status/limitations |
|---|
| Hydroxyurea | Stress
erythropoiesis; NO-sGC-cGMP signaling; ribonucleotide reductase
inhibition; indirect epigenetic effects (28,32,33) | Widely used;
variable response; requires monitoring; cytopenias |
|
Decitabine/5-azacytidine (DNMT
inhibitors) | Demethylation of
γ-globin promoter (28) | Increases HbF but
limited by toxicity; experimental/limited trials |
| Short-chain fatty
acids (Butyrates) | Histone
acetylation; chromatin relaxation (28,36) | Strong induction
in vitro/early trials; transient response; limited by
pharmacokinetics; inconsistent results across large clinical
trials |
| Pan-HDAC inhibitors
(vorinostat/panobinostat) | Broad histone
acetylation; open chromatin (28) | Proof of concept in
small trials; toxicity; not suitable for long-term use |
| Selective HDAC1/2
inhibitors | Targeted histone
acetylation (44) | Preclinical stage;
promising selectivity; human data lacking |
6. CRISPR-associated protein 9
The CRISPR/Cas9 technique can be used to edit the
epigenome and modify methylation patterns of DNA or histone changes
in the γ-globin gene locus. It enables precision genome editing to
disrupt HbF repressors or mimic the hereditary persistence of fetal
hemoglobin (45). Preclinical and
early clinical research has shown that targeting BCL11A or its
enhancer, ZBTB7A, or altering γ-globin promoters can successfully
regenerate HbF (46). Gene therapy
is probably safer than allogenic hematopoietic stem cell
transplant, though it is associated with adverse effects and is
expensive (47).
CRISPR/Cas9 identified nuclear factor 1A and nuclear
factor 1X as HBG1/2 repressors that are cooperative and expressed
at higher levels in adult erythroid cells than in fetal cells.
These transcription factors inhibit HBG1/2 and promote BCL11A
expression, playing a vital role in the fetal-to-adult hemoglobin
transition (48). A CRISPR/Cas9
screen demonstrated that globin gene switching is affected by
ubiquitin-proteasome components, with von Hippel-Lindau ubiquitin
ligase (VHL E3) depletion stabilizing hypoxia-inducible factor 1α,
which initiates the transcription of the γ-globin gene through
enhanced chromatin accessibility and transcriptional activators.
This implies that prolyl hydroxylase domain enzyme inhibition or
hypoxia may be used as therapy for β-hemoglobinopathy (49).
Frati et al (50) employed CRISPR/Cas9 gene editing to
target lymphoma-related factor (LRF) repressor sites in γ-globin
promoters, effectively reactivating HbF expression. This genome
editing strategy in patient-derived HSPCs and healthy donor cells
results in a significant HbF production and a high disruption of
lymphoma-related factor binding sites (LRF BS). In SCD HSPCs, LRF
BS disruption was more effective but also decreased myeloid bias
and engraftment. Genes linked to inflammatory reactions and DNA
damage were upregulated during the editing process (50). Furthermore, the USA and UK
authorized the commercial gene therapy product, Casgevy, a
CRISPR-based treatment that targets BCL11A, for use in
2023(51). Despite this
achievement, a number of obstacles still limit its clinical
application: Patients must be at least 12 years old to be eligible;
there are safety concerns about potential mosaicism and off-target
effects; and the sustained effectiveness of HbF induction over time
is unclear. Moreover, high costs and infrastructure demands pose
substantial obstacles to worldwide access, especially in
sub-Saharan Africa, where the prevalence of SCA is high.
Additionally, ethical concerns have been raised, particularly in
light of the possibility of germline editing, which might bring
heritable modifications into the human genome (52).
7. Future perspectives in the development of
epigenetic therapy
Large-scale, long-term clinical trials are required
to validate preclinical results and prove efficacy and safety in
humans. Ethical issues also need to be addressed, particularly in
relation to fair access, the possible unintended consequences of
genome editing, and the necessity of clearly outlining the
advantages, disadvantages, and available options when treating
pediatric patients. Future studies should therefore ensure safety,
improve selectivity, optimize delivery strategies, lower expenses
and guarantee access to innovative treatments. Researchers,
clinicians and policymakers must work together to make sure that
discoveries result in real benefits for patients with SCA
worldwide.
8. Study limitations and conclusion
The present review is based on preclinical studies
and early-phase trials. The lack of specificity in a number of
epigenetic agents poses safety issues. Furthermore, accessibility
and cost barriers restrict the potential of CRISPR treatments. The
regulatory network that controls γ-globin is still not fully known,
and there is still no explanation for the variation in patient
response.
Clinical relevance and translational
challenges
Although hydroxyurea is a key therapy, its variable
efficacy and side-effects pose a challenge. DNMT and HDAC
inhibitors are hindered by their toxicity, and CRISPR-based
therapies such as Casgevy hold promise; however, high costs and
complexity persist. These translational hurdles need to be overcome
to demonstrate clinical effectiveness, particularly in areas with
limited resources and high prevalence of the disease.
In conclusion, epigenetic modification provides a
compelling approach for the treatment of SCA via HbF reactivation.
Advances in pharmacology and genome editing have sped up clinical
translation. Selective HDAC1/2 inhibition and CRISPR/Cas9-based
treatments are particularly promising. To establish HbF
reactivation as a safe, efficient and widely available treatment
for SCA, further research on precision gene editing and specific
epigenetic modulators is mandatory.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
SAA was involved in the conceptualization of the
study, and in the drafting and editing of the manuscript. FB and
AYA were involved the reviewing and editing of the manuscript. All
authors have read and approved the final manuscript. Data
authentication is not applicable.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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