Non-toxic curative option for patients with genetic disorders

Abstract

In The Lancet, the FANCOLEN-1 study by Paula Río and colleagues2 took the approach, and risk, of infusing genetically modified cells into patients with Fanconi anaemia without any previous conditioning.2 Patients with this rare disease encounter major toxicities following exposure to cytotoxic agents due to their impaired DNA repair mechanisms.3 Only the well-defined Fanconi anaemia complementation group A (with mutations in FANCA) was selected for their clinical trial;2 it is the most frequent variant (60–80% of patients with Fanconi anaemia), with early disease onset, and a high incidence of leukaemia and solid tumours.4,5 In these patients, genomic instability often leads to bone marrow failure (BMF). [...]it is associated with morbidity with grade 3–4 acute and chronic graft-versus-host disease of 12% and 8%, respectively, and treatment-related mortality ranging from 5% to 18% with ASCT from a matched related donor, and 14% to 47% from an unrelated donor.8,10 Almost all transplant patients receive chemotherapy conditioning with approximately 10% receiving radiation therapy.11 According to the EBMT registry (509 patients), the 15-year cumulative incidence of secondary malignancy has been reported at 21% for patients alive 1 year or more after transplant, and 34% at 20 years.10 It is also noteworthy that ASCT for patients with DNA repair deficiencies calls for low intensity conditioning, experienced transplanters, and expertise when using haploidentical donors.12 Therefore, while curative, ASCT is also associated with substantial side-effects and mortality, underscoring the need for non-toxic treatment strategies. JGI/Jamie Grill via Getty Images I report grants paid to my institution from TheCell: Cell, Tissue and Gene Therapy Network, Fonds de recherche Quebec-Sante, BioCanRx, Cancer Research Society, Medicament-Quebec, Canadian Institutes of Health Research, HMR Foundation, Infilise Foundation, Quebec Ministry of Economy, Innovation and Energy and some of this funding is for clinical trials mostly in the area of cancer immunotherapy; speakers fees from CEL for health care; and advisory board fees from VOR.