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Acetylon Pharmaceuticals Publishes New Mechanism for the Treatment of Sickle Cell Disease/Beta-Thalassemia with Selective HDAC1/2 Inhibition in PLoS One


BOSTON – May 4, 2016 – Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, today announced the publication of preclinical data detailing a novel mechanism for the potential treatment of sickle cell disease/beta-thalassemia by the selective inhibition of HDACs 1 and 2 (HDAC1/2). The article titled, “Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2” was published in the online peer-reviewed journal PLoS One.

Acetylon is developing a series of selective HDAC1/2 inhibitors for the treatment of sickle cell disease and beta-thalassemia, two blood disorders with the highest prevalence worldwide of any genetic disease. Elevated levels of normal fetal hemoglobin (HbF) protein can reduce disease severity in patients with sickle cell disease or beta-thalassemia by replacing missing or defective adult hemoglobin. Previous preclinical studies have demonstrated that non-selective HDAC inhibition induces HbF; however, the use of available non-selective HDAC inhibitors in the clinical setting has been associated with significant toxicity and adverse events. Recent reports have also shown that genetic knockdown of either HDAC1 or HDAC2 gene expression is sufficient to increase HbF in adult erythroid (red blood cell) progenitor cells. As reported in the manuscript, studies demonstrated that selective inhibition of HDAC1/2 with the proprietary tool compound ACY-957 potently induced HbF in human blood cells from sickle cell patients cultured ex vivo. Selective inhibition of HDAC1/2 is expected to reduce toxic side effects versus non-selective HDAC inhibitors.

Acetylon researchers reported that the production of HbF is mediated in part by increased expression of GATA2, a critical regulator in blood cell development. Gene expression profiling experiments identified enhanced expression of GATA2 in response to HDAC1/2 inhibition by ACY-957. This finding was supported by genetically overexpressing GATA2, which led to an increase in gamma-globin (HBG) mRNA; HBG protein pairs with alpha-globin to yield HbF. Conversely, the induction of HBG gene expression by ACY-957 was reduced by genetic knockdown of GATA2 expression. In addition, chromatin immunoprecipitation and sequencing (ChIP-Seq) experiments demonstrated that HDAC1/2 inhibition led to increased histone acetylation and increased GATA2 binding at known GATA2 autoregulatory DNA regions. Together, these data demonstrate that chemical inhibition of HDAC1/2 induces HBG, leading to increased levels of HbF, and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of GATA2 gene expression.

“The results of these studies provide a deeper understanding of the mechanism through which HDAC inhibition leads to elevated fetal hemoglobin and describe a potentially novel therapeutic avenue for treating hemoglobinopathies,” said Jeff Shearstone, Ph.D., Senior Scientist at Acetylon and corresponding author of the paper.

“While others have shown that HBG and HbF can be induced by non-selective histone deacetylase (HDAC) inhibitors, these have been clinically associated with significant toxicity and adverse events. These new data will inform the design of future programs at Acetylon as we build an industry-leading portfolio of selective HDAC inhibitors to provide novel and better-tolerated therapeutic options for patients,” said Matthew Jarpe, Ph.D., Associate Vice President of Biology at Acetylon. “Additionally, the induction of GATA2 by selective HDAC1/2 inhibitors may have broader implications for the treatment of diseases or disorders associated with GATA2 deficiency, including myelodysplastic syndrome and acute myeloid leukemia, and we look forward to continued exploration of this relationship in the context of additional indications.”

About Epigenetics

Epigenetics is the covalent modification of DNA, RNA or protein, resulting in changes to the function and/or regulation of these molecules without altering their primary sequences. Epigenetic modifications are often stable and may be transmitted to future generations, but in other instances, they are dynamic and change in response to environmental stimuli. Epigenetic changes are a normal part of many biological processes. They allow stem cells to differentiate into more-specialized cell types, but they can also lead to cancer and other diseases. Several different classes of drugs are effectors of epigenetic changes in the human body including HDAC inhibitors.

About Acetylon

Acetylon Pharmaceuticals, Inc., based in Boston, Massachusetts, is a leader in the development of novel small molecule drugs targeting epigenetic mechanisms for the enhancement of therapeutic outcomes in cancer and other critical human diseases. The Company’s epigenetic drug discovery platform has yielded a proprietary portfolio of optimized, Class I and Class II histone deacetylase (HDAC) selective compounds for oral administration. Alteration of HDAC regulation through selective HDAC inhibition is thought to be applicable to a broad range of diseases including cancer, sickle cell disease and beta-thalassemia, and autoimmune and neurodegenerative diseases. Acetylon’s lead drug candidate, ricolinostat (ACY-1215), is a selective HDAC6 inhibitor currently in Phase 2 clinical development for the treatment of multiple myeloma. In 2013, the Company announced a strategic collaboration agreement with Celgene Corporation, which includes an exclusive option for the future acquisition of Acetylon by Celgene. Acetylon’s scientific founders are affiliated with Harvard University, the Dana-Farber Cancer Institute, the Massachusetts General Hospital, and Harvard Medical School. www.acetylon.com




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MacDougall Biomedical Communications

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