Despite many reports of putative stem-cell-based treatments in genetic and degenerative disorders or severe injuries, the number of proven stem cell therapies has remained small. In this Review, we survey advances in stem cell research and describe the cell types that are currently being used in the clinic or are close to clinical trials. Finally, we analyse the scientific rationale, experimental approaches, caveats and results underpinning the clinical use of such stem cells.

Advances in stem cell research and therapeutic development

Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies. Advances in the design of vectors based on retroviruses, such as lentiviruses and gammaretroviruses, have led to improvements in the safety and stability of gene therapies directed at haematopoietic stem and progenitor cells. In this Review, Cavazzana and colleagues discuss the results from recent clinical trials of retroviral vectors for the treatment of genetic disorders, including severe combined immunodeficiencies and β-haemoglobinopathies (β-thalassaemia and sickle cell disease). They highlight the progress made and the remaining challenges in applying gene therapies more broadly.

Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges.

Haematopoietic stem and progenitor cell (HSPC) gene therapy has emerged as an effective treatment modality for monogenic disorders of the blood system such as primary immunodeficiencies and β-thalassaemia. Medicinal products based on autologous HSPCs corrected using lentiviral and gammaretroviral vectors have now been approved for clinical use, and the site-specific genome modification of HSPCs using gene editing techniques such as CRISPR-Cas9 has shown great clinical promise. Preclinical studies have shown engineered HSPCs could also be used to cross-correct non-haematopoietic cells in neurodegenerative metabolic diseases. Here, we review the most recent advances in HSPC gene therapy and discuss emerging strategies for using HSPC gene therapy for a range of diseases.

Gene therapy using haematopoietic stem and progenitor cells

Background Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Methods We treated 50 patients w...

https://www.nejm.org/doi/suppl/10.1056/NEJMoa2027675/suppl_file/nejmoa2027675_data-sharing.pdf

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

Here I review the scientific background, current stage of development and future perspectives that I foresee in the field of genetic manipulation of hematopoietic stem cells with a special emphasis on clinical applications.

https://www.embopress.org/doi/pdf/10.15252/emmm.201809958

Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives

s-thalassemia is caused by s-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express s-globin represents a potential therapeutic option. We treated three adults and six children with s0 or severe s+ mutations in a phase 1/2 trial (
 NCT02453477
 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6–76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10–1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome. In a phase 1/2 clinical trial, gene therapy with autologous hematopoietic stem cells significantly reduced transfusion requirement in adults and children with transfusion dependent s-thalassemia.

Alessandra Bergami

Papers

Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia.