Gene Therapy Studies in Hemoglobinopathies: Successes and Challenges
Authors: Cavazzana Marina 
Published: October 2019

Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) from bone marrow or umbilical cord blood is currently the only curative treatment for hemoglobinopathies. However, only a small percentage of patients can undergo this procedure because (i) it can only be performed in specialized units, and (ii) the populations affected by these diseases are poorly represented in the international registry of HSC donors. Gene therapy using autologous HSC is a powerful alternative to allogeneic HSCT. It circumvents the need for a matched, unrelated donor and thus avoids the risk of graft-versus-host disease and graft rejection after HSCT. Furthermore, the conditioning regimen required to allow the engraftment of genetically modified cells does not include immunosuppressive drugs responsible for infectious complications. Hence, the gene therapy procedure can be performed by many pediatric and adult hematological units - even those with limited or no expertise of allogeneic HSCT. The absence of any treatment-related deaths in gene therapy trials to date and the increasing safety of this therapeutic approach are now enabling its rapid, broad application worldwide. Lentiviral vectors (LVs) fulfill the complex criteria required for a successful outcome in gene therapy for β-hemoglobinopathies. The use of self-inactivating (SIN) LVs (generated by the deletion of viral promoters/enhancers in the U3 region of the 3' long terminal repeat) has greatly improved vector safety. In view of the results obtained since 2007, SIN LVs vectors appear to be associated with a much lower risk of insertional mutagenesis than first-generation gamma retroviral vectors. Clinical trials of globin-expressing LVs are now under way at several sites in Europe (Paris and Milan) and the United States. The initial results are encouraging with regard to the achievement of transfusion-independence. Despite these promising results, some issues deserve further investigation (e.g. optimization of the conditioning regimen, mobilization protocol, vectors and transduction protocol). The objective of the conditioning regimen is to efficiently destroy the diseased hematopoietic stem cells (using toxic and/or depleting monoclonal antibodies) while avoiding off-target toxicity in other organs. This should protect the patient's fertility, and prevent mucositis and liver toxicity. Secondly, the characteristic dyserythropoeisis in the patients' bone marrow must also to be taken into account when seeking to obtain the requisite number of hematopoietic stem cells. The hypercellular erythroid bone marrow compartment and the microenvironment are key parameters in this setting. There is currently an intense, fruitful debate as to the best mobilizing factor for these patients. Furthermore, the characteristic inflammatory context in Hb SS patients should allow the use of anti-inflammatory molecules before harvesting. Lastly, genome editing and homologous recombination technologies have undergone spectacular developments over the last couple of decades. In view of the impressive progress recently reported for the gene addition strategy, offering gene editing approaches to patients affected by β-hemoglobinopathies would pose a number of ethical and medical questions.

Disclosures
No relevant conflicts of interest to declare.