Gene and Cell Therapies for Beta-globinopathies

Hemoglobin defects, specifically sickle cell disease & thalassemia, combined, constitute the most common monogenic disorders in the world. In fact, nearly 2% of the world's population carries a globin gene mutation. The transfer of the corrective globin gene through the HSC compartment by allogeneic HSC transplantation (HSCT) has already proven curative in both SCD and thalassemia patients, and provides the proof of concept that genetic manipulation of the defective organ might be equally therapeutic. However, procedural toxicities and the requirement of an HLA-matched sibling donor limit this approach to a fraction of affected individuals. The editors review the progress & the state of the field in HSCT for hemoglobinopathies & shed light on the major changes expected in the next decade. Although allogeneic HSCT is a curative option, it is limited by the availability of matched donors, which are often available only to 15-20% of patients. An alternative to allogeneic HS

CT is genetic correction of autologous HSCs, to overcome donor availability & immune side effects. This Book reviews the progress made on additive gene therapy approaches & the current state of the field. Finally, targeted genetic correction is emerging as a novel therapeutic strategy in the hemoglobinopathies. Although ideal, the inefficiency of targeted correction was rate limiting for translation of this technology to the clinic. With advancements in zinc finger nucleases and TALE endonuclease mediated targeted correction, correction frequencies in hematopoietic stem cells is now reaching levels that may become clinically relevant. Furthermore, the ability to generate autologous embryonic stem cell like cells from primary somatic cells (skin fibroblasts or hematopoietic cells) of the affected individual has allowed for the potential application of genetic correction strategies.This Book reviews upcoming genetic strategies to reactivate fetal hemoglobin production and research advances.

Punam Malik received her M.D. degree from Lady Hardinge Medical College, University of Delhi, India. She completed a pediatric residency at Kalawati Saran Children;s Hospital, Delhi and at Children’s Hospital Los Angeles, Los Angeles, California, and then then trained in hematology-oncology at Children’s Hospital Los Angeles, where she served as fellow, Assistant Professor from 1999-2005 and a tenured Associate Professor in 2006 at CHLA, University of Southern California. She joined Cincinnati Children’s Hospital Medical Center and the University of Cincinnati in 2007 as the Program Director of the Gene and Cell Therapy Program and in 2008, she became the director of the Translational Core Laboratories at CCHMC. In 2010, she became a Professor of Pediatrics. In 2012, she became the director of the Cincinnati Comprehensive Sickle Cell Center, and in 2014 she became the Marjorie Johnson Endowed Professor of Gene and Cell Therapy. Her group focuses on the pathobiology of sickle cell disease and thalassemia, identifying mechanisms of organ pathologies in sickle cell disease, and developing curative strategies for hemoglobinopathies and other hematopoietic stem cell disorders through transplantation of genetically modified autologous bone marrow stem cells.

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