Novel HDAC Inhibitors for Treatment of Hemoglobinopathies

Project Summary
Induction of normal but developmentally silenced fetal globin expression reduces
anemia and ameliorates clinical severity in the beta hemoglobinopathies HDACs
and are components of the NURD repressor complex which promotes silencing of
fetal globin in adult cells Prior generation HDAC inhibitors have increased fetal globin in
patients but had limitations for pharmaceutical application and required intermittent
administration due to anti proliferative effects Cetya has generated a library of high
potency HDAC inhibitors which can be readily modulated in chemical structure and has
demonstrated their efficacy in inducing fetal globin induction in normal human erythroid
cells including a select few candidates which do not shown undesirable growth inhibitory
effects at fetal globin inducing concentrations The laboratory of Dr Perrine at Boston
University will evaluate these candidates in progenitor cells cultured from sickle cell
patients Dr Perrine has extensive experience in developing treatments for sickle cell
and beta thalassemia This collaboration will explore this new high potency generation
in HDAC chemistry to advance a therapeutic class to the clinic The studies proposed
will identify an optimal HDAC inhibitor for subsequent development to an IND
Aim To evaluate HDAC inhibitors for magnitude of fetal globin induction and anti
proliferative effects in sickle cell erythroid progenitors and identify an optimal candidate
for preclinical development
Aim To increase the production scale of the selected candidate to support testing in
IND required toxicology studies
This proposal will evaluate novel histone deacetylase HDAC inhibitors for a new
medical use in hemoglobinopathies serious blood diseases which confer life long
morbidity and early mortality an annual US healthcare burden of andgt $ Billion and high
childhood mortality internationally Preliminary evaluation of these HDAC inhibitors has
demonstrated promising activity in the upregulation of fetal hemoglobin at concentrations
where the relative absence of cellular toxicity is evident Upon completion of the
proposed studies the most potent agent will be tested in animal models and if
successful rapidly advanced into human clinical trials