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Over the past decade, therapy based on gene addition to hematopoietic stem progenitor cells (HSPCs) has achieved unprecedented curative outcomes for several genetic diseases, such as X-linked severe combined immunodeficiency (X-SCID) (1), adenosine deaminase deficiency (2), metachromatic leukodystrophy (3), hemoglobinopathies (4), and Wiskott–Aldrich syndrome (WAS) (5). Recent developments in genome-editing technology are likely to further broaden the use of HSPCs harvested from patients and then genetically corrected ex vivo. Despite this undeniable progress, gene therapy continues to face a number of important challenges which, if not resolved, will slow the clinical development of this approach. These challenges cover the full spectrum of translating research findings to clinical practice, from purely scientific questions through to social, ethical economic issues, and public health issues. In this editorial for the newly launched section of Innovative Therapies in Frontiers in Medicine, I list and briefly discuss some of these often interconnected challenges, with a view to encouraging fruitful dialog with the readers of this new journal. The use of autologous gene-corrected HSPCs eliminates the risk of alloreactive immune responses (such as graft rejection and graft-versus-host disease) and significantly decreases the risk of infectious complications (since the administration of immunosuppressive and cytotoxic drugs is not required). Despite the avoidance of these potentially life-threatening complications, gene-modified autolo-gous HSPCs need a conditioning regimen to make space for the corrected cells, and this conditioning regimen is responsible for acute and chronic toxicity (6). The acute toxicity mainly corresponds to grade 3 mucositis and a risk of infections, where as chronic toxicity includes infertility, although germ cells are cryopreserved whenever possible and as a function of the patient's age. Even though severe adverse events associated with the conditioning regimen may be acceptable in light of the benefit/risk ratio, they constitute a hurdle to the worldwide application of this strategy. One possible solution to this problem is the use of drugs that are able to specifically target HSPCs in the bone marrow niche while sparing all the non-hematopoietic tissues. A conditioning regimen that minimizes off-target toxicity and immunosuppression while enabling the efficient engraftment of gene-modified cells would greatly facilitate the expansion of this curative approach. Progress in this field is expected very soon (7). In terms of vector design, the use of latest-generation, self-inactivating retroviral vectors has significantly reduced the likelihood of insertional mutagenesis (8). An increasing number of patients have been transplanted using this self-inactivating vector strategy since 2006, …

Innovations Needed for Effective Implementation of Ex Vivo Gene Therapies