Discovery of novel fetal hemoglobin repressor may provide ‘new avenues’ for sickle cell disease treatment
ORLANDO — Researchers identified the protein nuclear factor IX as a novel repressor of fetal hemoglobin, a discovery that could lead to the development of new treatments for sickle cell disease, according to data presented at ASH Annual Meeting and Exposition.
The investigation showed that lowering levels of nuclear factor IX (NFIX) induced induction of fetal hemoglobin when assessed by in vitro chromatin accessibility mapping of primary erythroid cell populations.
“Our company has a larger effort in sickle cell disease centered around the idea of increasing fetal hemoglobin, so this research was one prong of that effort to see if we could apply some of the core competencies of our research platform to discover something new,” Jeffrey R. Shearstone, PhD, director of molecular and cellular biology at Syros Pharmaceuticals, told Healio.
Shearstone said his company is “well-equipped” to use state-of-the-art high-throughput genomic profiling technologies to identify potential modulators of genes in patients with sickle cell disease.
“We need to understand more about the mechanism by which NFIX silences fetal hemoglobin and to understand whether NFIX interacts with other fetal hemoglobin repressors, and if those repressors intersect at any point,” he said, adding that researchers also need to identify the best target candidates and the best way to evaluate those targets.
“We are very well-equipped to discover and validate a lot of these hemoglobin repressors,” Shearstone said. “The challenges in developing a drug for sickle cell disease are similar to the challenges facing any other disease modality. Success depends on our ability to identify a compound that has the function that we want. We are in a good position to do this and have many interesting avenues to explore in the development of one of these molecules.”
Implicating NFIX as hemoglobin repressor
In the study, the investigators cultured human CD34-positive stem and progenitor cells to produce adult red blood cells. The umbilical cord blood-derived cells expressed mostly fetal hemoglobin, whereas bone marrow-derived cells expressed primarily adult hemoglobin.
Shearstone and colleagues then generated chromatin accessibility maps from purified, stage-matched cells to compare fetal and adult cells and identify transcription factors that regulated the repression of human fetal hemoglobin.
The results showed enriched nuclear factor I binding motifs under Assay for Transposase Accessible Chromatin (ATAC) sequencing peaks that appeared larger in adult-state cells. In addition, researchers observed increased accessibility at the NFIX promoter and elevated NFIX mRNA levels in adult-state cells.
The investigators then tested the hypothesis that NFIX represses fetal hemoglobin by using primary cells and cell lines to show that NFIX knockdown leads to the induction of human fetal hemoglobin. The results compared favorably with BCL11A and ZBTB7A — previously known repressors of human fetal hemoglobin. The lowering of NFIX levels also induced human fetal hemoglobin level increases consistent with clinical cure of sickle cell disease (97% F cells; 40% fetal hemoglobin).
“By putting a new fetal hemoglobin repressor on the table, one that may be a singular target or work in concert with other repressors, it provides potential new avenues for developing a small molecule to treat sickle cell disease,” Shearstone told Healio, cautioning that this still an early discovery that needs to be thoroughly vetted and tested in future research.
“We want to be cautious about the discovery, but we have a lot of reason to be optimistic about the work we have done in a relatively short amount of time,” he said.
Small molecules in the age of gene therapy
Given the focus paid to gene therapy for the treatment of sickle cell disease at this year’s ASH Annual Meeting, Healio asked Shearstone if small molecule agents still had a role in treatment of the disease. He acknowledged that this question has come up frequently in recent years.
“There is a place for small molecules because of the limitations of gene therapy,” Shearstone told Healio.
These limitations include accessibility and eligibility issues, he explained.
“Not everyone will be eligible for stem cell transplants; not all patients will have access to centers of excellence that perform gene therapies,” Shearstone said.
His vision for the future is a small molecule agent that would serve as a first line of treatment for sickle cell disease.
“Then there are patients who will not want to undergo the risk of a bone marrow transplant, so I see small molecule therapies being complementary to other approaches in such a way that patients would try a small molecule first and if they do not respond to that therapy, they can move on to more specific gene therapies as a last line of defense,” he added. – by Drew Amorosi
Chaand M, et al. Abstract 812. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Shearstone is employed by and has equity ownership in Syros Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.