Targeting ZNF410 for fetal hemoglobin induction in beta-hemoglobinopathies
Background
β-hemoglobinopathies, such as sickle cell disease and β-thalassemias, are genetic disorders characterized by defective hemoglobin production, resulting in anemia and impaired oxygen delivery. These conditions affect millions worldwide, posing significant health burdens and a clinical unmet need for effective and safe treatments. The current standard of care involves drugs like hydroxyurea to induce fetal hemoglobin (HbF) production, but these treatments often lead to side effects and inconsistent efficacy. Improved approaches are needed to reliably boost HbF levels with minimal adverse effects.
Induction of fetal γ-globin expression could bypass the underlying β-globin molecular defects and ameliorate the pathophysiological cascades that result in elevated morbidity and mortality. Critical regulators of the switch from fetal to adult globin expression have been identified, including the DNA-binding transcription factors (TFs) BCL11A, ZBTB7A and the nucleosome remodeling and deacetylase (NuRD) chromatin complex. However, the pleiotropic molecular, cellular and organismal effects of each of these HbF repressors make the therapeutic window uncertain and the risk of undesired on-target liabilities considerable. Therefore, a new target is needed with a wide therapeutic index through which inhibition of function could be tolerated across a diverse set of cellular contexts.
Technology Overview
Using CRISPR screening, researchers identified a novel therapeutic target: zinc finger protein 410 (ZNF410), a novel HbF repressing TF that is dispensable for erythroid maturation, thereby paving the way for safer and more effective HbF induction in patients with β-hemoglobinopathies. By disrupting ZNF410 activity through gene editing techniques or specific inhibitors, HbF levels can be increased without the risks associated with complete disruption of critical co-factor pathways.
This study also found ZNF410 represses HbF level in adult-stage cells by devoted maintenance of NuRD subcomplex levels through binding an extraordinary cluster of sites upstream of CHD4 (the catalytic NuRD subunit). Proof-of-concept studies demonstrated that inhibiting ZNF410 reduces CHD4 nucleosome remodeler expression by approximately 60%, effectively de-repressing HbF without inducing cellular toxicity. Experimental models, including mice with constitutive deficiency of the homolog Zfp410 and xenotransplantation of gene edited ZNF410 knockout primary human hematopoietic stem and progenitor cells (HSPCs) to immunodeficient NBSGW mice, confirmed that ZNF410 is an evolutionarily conserved HbF repressor that is not essential for vertebrate survival, or for human erythropoiesis and hematopoiesis. These features show ZNF410 as a new target for HbF induction for the beta-hemoglobin disorders with a wide therapeutic index.
Applications
- Treatment of β-hemoglobinopathies: Specifically advantageous for conditions such as sickle cell disease, sickle cell anemia, and various forms of β-thalassemia.
Advantages
- Enhanced Efficacy: Provides a targeted method for substantially increasing HbF levels more reliably than current therapies.
- Safety Profile: Avoids the adverse effects associated with standard treatments like hydroxyurea, offering a potentially broader therapeutic window; avoid on-target liabilities of other major regulators of adult-stage HbF silencing TFs.
- Versatility: Applicable across diverse patient populations and cellular contexts, making it suitable for widespread use.
Publications
- Vinjamur DS, Yao Q, Cole MA, McGuckin C, Ren C, Zeng J, Hossain M, Luk K, Wolfe SA, Pinello L, Bauer DE. ZNF410 represses fetal globin by singular control of CHD4. Nat Genet. 2021 Apr 15. doi: 10.1038/s41588-021-00843-w. Online ahead of print. PMID: 33859416.
