Susan Perrine

Susan Perrine S.M., M.D. is a Pediatric Hematologist Oncologist who obtained degrees, residency, and fellowship training from Harvard School of Public Health, Tufts University School of Medicine, Tufts Medical Center, Children’s Hospital Boston/ Dana Farber Cancer Institute, and Harvard Medical School. She is currently Professor of Pediatrics, Medicine, and Experimental Pharmacology at Boston University School of Medicine. She has founded 3 biotechnology companies to develop therapeutics to modulate gene expression for treatment of hemoglobinopathies and viral malignancies. Her current work focuses on tailoring therapeutics to genetic modifier profiles for optimal responses.

Abstract: HbF reactivation: a pipeline for epigenetic and targeted therapeutics Susan P. Perrine MD and David H.K. Chui MD, Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, MA.

Sickle cell disease is a WHO-designated global health burden with serious morbidity and early mortality.  Fetal hemoglobin (HbF) is the most powerful modulator of the clinical severity of sickle cell anemia, with levels >20-30% associated with generally benign disease.  While HbF can be induced in many patients with hydroxyurea, most adults do not reach these ameliorating levels, and additional HbF-enhancing therapies are needed, particularly for use in combination regimens.  A challenge to successful application of HbF-inducing therapies is the broad genetic heterogeneity in baseline HbF levels, and, to date, unpredictable responsiveness to therapeutics among individual patients. Therapies tailored to genetic modifiers (QTL) which modulate baseline HbF levels may allow    optimal treatment selection for specific subsets of patients.  In analyses of patients enrolled on two clinical trials, we recently found that SNPs in 2 influential QTLs affecting HbF occur commonly, with BCL11A polymorphisms occurring in 20-30% of sickle cell or beta thalassemia patients.  Using molecular modeling and high-throughput screening of chemical libraries, we have discovered that other therapeutics (including 6 clinical-stage drugs, approved for other medical conditions) enhance HbF expression through different mechanisms, including displacement of a repressor complex containing HDAC-3 (RB7), or suppression of BCL11A mRNA (MS-275).  Two pan-HDAC inhibitors (Butyrate and MS-275) profoundly decrease the 3 BCL11A isoforms by 80-100% in erythroid progenitors, while other HDAC inhibitors (LBH389, SAHA) have no effect.  Decitabine, a potent hypomethylating agent  is being formulated for oral use.

MS-275, DLT, and RB7 increase g globin expression up to 5-6 fold in erythroid progenitors, whereas earlier generations induce by a mean of 2-fold.   Most new inducers have targeted effects, not affecting  histone acetylation or methylation.  In initial studies in sickle cell patients’ erythroid progenitors, responsiveness to the new HbF-inducers differ, with some drugs producing 3-fold induction over baseline in erythroid cells with standard QTL profiles, and lesser induction when SNPs in BCL11A are present, suggesting its effects are already somewhat neutralized.  A small but diverse pipeline of therapeutics now allows epigenetic and/or non-epigenetic g-globin induction. Individual therapeutics are being studied now in erythroid cells cultured from genotyped patients  to develop a basis for tailoring specific inducer combinations to QTL profiles and potentially will provide greater therapeutic benefit.


Scroll to Top