Gene therapy for PIDs: Progress, pitfalls and prospects

Abstract

Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future.

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

“…In these disorders, the hematopoietic stem cells are taken from the patient’s body and transduced, often with integrating viral vectors such as rRV and rLV and transplanted back into the patient. This is highly successful, as corroborated by recent regulatory approvals for adenosine deaminase (ADA)‐deficient severe combined immunodeficiency (SCID), and can provide a life-long cure for patients that cannot be treated with bone marrow transplantation [84,85]. …”

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

“…4 Moreover, LV trials for X-SCID, Fanconi anemia (FA), and other monogenetic defects were initiated. [5][6][7] Genetically modified HSCs should retain engraftment and functional properties similar to those of unmodified HSCs. They should be able to self-renew and to differentiate into all hematopoietic lineages.…”

B. Hofmann & K. Slagstad svarer:

“…For immunsvikt uten andre behandlingsmuligheter har man akseptert høyere risiko enn i de fleste andre kliniske studier av genterapi. Det er i slike studier de mest alvorlige, uønskede hendelsene er observert; med seks tilfeller av leukemi, ett med dødelig utgang 197,198 (se også pkt. 6.6).…”