Gene therapy
Gene therapy has been used successfully for both adenosine deaminase deficient SCID (ADA-SCID) and X-linked SCID.[56]Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol. 2008 Jul;15(4):375-80.
http://www.ncbi.nlm.nih.gov/pubmed/18536577?tool=bestpractice.com
[57]Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002 Jun 28;296(5577):2410-3.
http://www.ncbi.nlm.nih.gov/pubmed/12089448?tool=bestpractice.com
[58]Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58.
http://www.ncbi.nlm.nih.gov/pubmed/19179314?tool=bestpractice.com
In 2016, a gene therapy treatment protocol that modifies autologous stem cells to produce ADA (Strimvelis®) was approved in Europe for the treatment of ADA-SCID in those with no matching donor for stem cell transplant.[59]European Medicines Agency. New gene therapy for the treatment of children with ultra-rare immune disorder recommended for approval. April 2016 [internet publication].
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/04/news_detail_002504.jsp&mid=WC0b01ac058004d5c1
This recommendation was based on a study of 12 patients who received Strimvelis® gene therapy, all of whom were alive at an average follow-up period of 7 years. The first successful trial of gene therapy for X-linked SCID was reported in 2000.[56]Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol. 2008 Jul;15(4):375-80.
http://www.ncbi.nlm.nih.gov/pubmed/18536577?tool=bestpractice.com
Ten patients were treated; 8 patients had reconstitution of T-cell counts with normalised function and diversity. In addition, normal immunoglobulin levels were seen in most of the patients. Long-term follow-up (8 to 11 years) did not show genotoxicity.[60]Reinhardt B, Habib O, Shaw KL, et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood. 2021 Oct 14;138(15):1304-16.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525336
http://www.ncbi.nlm.nih.gov/pubmed/33974038?tool=bestpractice.com
Several patients with X-linked SCID developed leukaemia after gene therapy due to retroviral insertion and subsequent activation of proto-oncogenes.[56]Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol. 2008 Jul;15(4):375-80.
http://www.ncbi.nlm.nih.gov/pubmed/18536577?tool=bestpractice.com
By contrast, there have been no reports to date of leukaemia with gene therapy for ADA-SCID. New approaches using alternative delivery ways, such as lentiviral vectors and gene editing, are being investigated for X-linked SCID, Artemis-SCID, IL7R-SCID, RAG1-SCID, and RAG2-SCID.[61]Chetty K, Houghton BC, Booth C. Gene Therapy for inborn errors of immunity: severe combined immunodeficiencies. Hematol Oncol Clin North Am. 2022 Aug;36(4):813-27.
http://www.ncbi.nlm.nih.gov/pubmed/35773051?tool=bestpractice.com
JSP191
JSP191, a novel monoclonal antibody, is being studied in patients with SCID undergoing haematopoietic stem cell transplant (HSCT).[62]ClinicalTrials.gov. JSP191 antibody targeting conditioning in SCID patients. ClinicalTrials.gov identifier: NCT02963064. Nov 2021 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT02963064
JSP191 binds to CD117, which in turn blocks CD117 from binding to stem cell factor. Without this binding, haematopoietic stem cells are cleared from the bone marrow, allowing an empty space for donor or gene-corrected transplanted cells to engraft. JSP191 has received fast track designation from the US Food and Drug Administration for the treatment of patients with SCID undergoing HSCT.