Hematopoietic stem cell (HSC) gene therapy has been explored in the clinic for the last 20 years in attempt to treat hematological hereditary diseases. The recent review nicely summarizes clinical experience of HSC engineering and highlights the future directions.
We all remember a tragic adverse events in few clinical trials:
The toxicities associated with the γ-retroviral transduction of HSCs are the consequence of the semirandom pattern of retroviral integration and the presence of strong enhancers in the proviral LTR, resulting in obligatory insertional mutagenesis. Activation of proto-oncogenes in the genomic neighborhood is the most dreaded consequence. The direst outcome, frank leukemic transformation, has been dramatically illustrated in X-SCID and WAS, where so far 5 of 20 and 1 of 10 patients, respectively, have developed clonal T-cell leukemias.
The authors indicate that at the end of 2 decades of trials and errors, now we’re at a crossroads:
As the chapter on LTR-driven vectors comes to a close, several new chapters are already being written. The immediate future will evaluate SIN-γRVs, SIN-LVs, and lineage-restricted vectors, all of which should reduce the risk of trans-activating proto-oncogenes after semirandom integrations. Next, targeted gene delivery systems have the potential to further reduce the risk of integrating vectors at undesirable chromosomal locations. Later, if pluripotent stem cells fulfill their promise for the generation of HSCs and if the genotoxicity issues of their own prove not to be prohibitive, genetically corrected cells in which vector integration or gene repair can be fully ascertained before cell infusion will become available.
About the difficulties in pursuing a new approaches:
Off-target genotoxicity and efficiency of long-term HSC correction will be difficult to assess in xenograft models and will require both large-animals studies and pilot clinical trials in a patient population with sufficiently serious disease complications to justify introduction of these potentially risky approaches.
… the generation of human HSCs from ES or iPS cells remains an enigma, one that will hopefully soon be resolved.
Another game-changing advance would entail the ability to reprogram human adult HSCs to an expandable state without diminishing their long-term self-renewal properties and their safety, a goal that has remained elusive to date.
Excellent review! Highly recommended!