Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned

Abstract

The use of allogeneic hematopoietic stem cells (HSCs) to treat genetic blood cell diseases has become a clinical standard but is limited by availability of suitable matched donors and potential immunologic complications. Gene therapy using autologous HSCs should avoid these limitations and thus may be safer. Progressive improvements in techniques for genetic correction of HSCs, by either vector gene addition or gene editing, are facilitating successful treatments for an increasing number of diseases. We highlight the progress, successes, and remaining challenges toward development of HSC gene therapies and discuss lessons they provide for development of future clinical stem cell therapies.

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury

“…Irradiation or chemotherapy followed by allogenic stem cell transplantation is a major therapeutic approach for the treatment of leukemia and other malignant and non-malignant diseases (Copelan, 2006;Ferrara et al, 2009;Kondo et al, 2003;Morgan et al, 2017;Rafii and Lyden, 2003;Thomas et al, 1975). High transplantation efficiency is beneficial for both patients and donors (Ballen et al, 2013;Copelan, 2006; Ratajczak and Suszynska, 2016).…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…The HSCs can either originate from a suitable donor individual, or patient's own HSCs can be corrected in vitro (e.g. by gene therapy) and then back-transplanted into the patient in an autologous manner [107]. In the future, it may also be possible to correct the autologous HSCs by genome editing technologies such as CRISPR/Cas [107].…”

“…by gene therapy) and then back-transplanted into the patient in an autologous manner [107]. In the future, it may also be possible to correct the autologous HSCs by genome editing technologies such as CRISPR/Cas [107]. However, due to the unpredictable and sometimes imprecise outcome of genome editing techniques, such as altered splicing or off-target effects [108], these technologies will still require further research before they can be safely applied on patients.…”

Minimal conditioning in Fanconi anemia promotes multi‐lineage marrow engraftment at 10‐fold lower cell doses

“…Alternatively, new methods using gene therapy approaches for BMT have been advancing in clinical trials at several institutions worldwide . These encompass autologous hematopoietic stem cell (HSC) transplantation where a functional version of a defective gene is inserted into cells during ex vivo culture and then reinfused back into patients . For FA patients, these autologous transplants are typically performed in expedited protocols minimizing the time that the patient's cells are cultured and exposed to oxidative stress ex vivo because this can lead to additional accrued DNA damage .…”