Short- and medium-term safety profile of ADA-SCID gene therapy described

Short- and medium-term safety profile of ADA-SCID gene therapy described

Published Date: 4/4/18

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medwireNews: Researchers report on the short- and medium-term adverse event (AE) profile of gene therapy with autologous retroviral vector-transduced CD34+ cells in a cohort of 18 patients with adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID).

The patients received transduced CD34+ cells at doses ranging from 0.9 to 18.2×106 cells/kg at a median age of 1.7 years (range 0.5–6.1 years), in all cases after preconditioning with busulfan. The majority (n=15) had received prior enzyme replacement therapy (ERT) with polyethylene glycol-modified-ADA and four patients had a history of unsuccessful haploidentical haematopoietic stem cell transplantation (SCT). The treatment was successful in all but three children, who had poor immune reconstitution following gene therapy and required additional treatment. The team notes that all patients were alive at a median follow-up of 6.9 years.

Over this period, all patients experienced AEs, which were generally of grade 1 or 2, although 39 serious AEs occurred in 15 patients post-treatment, report Alessandro Aiuti (San Raffaele Telethon Institute for Gene Therapy, Milan, Italy) and team. The incidence of AEs tended to be highest during treatment and at the 3-month follow-up, with lower rates reported at the 3- and 7-year timepoints and beyond.

Infections occurred in all participants, and 24 of the serious AEs were infections, all of which resolved, they add. There were also 30 incidences of opportunistic infections, the majority of which were of grade 1 or 2, and again all had resolved by data cutoff.

Following gene therapy, 12 children experienced 26 AEs related to autoimmunity, of which seven were serious AEs. The most common autoimmunity-related AE was grade 1 antinuclear antibody positivity, five incidences of which were reported in as many patients.

Hepatic events were also observed during or after busulfan conditioning and gene therapy, with 34 events in 12 patients. Again the majority of events were of grade 1, and just one case of autoimmune hepatitis was classed as a serious AE.

Aiuti et al report that 13 patients exhibited neurological and hearing impairments during the post-gene therapy follow-up period, but as such manifestations were also frequent at baseline (observed in 14 children), the researchers say that they are “unable to differentiate between the underlying disease state and [gene therapy]-related procedures/medications […] as potentially contributing factors.”

Of note, no events indicative of leukaemic transformation have been reported in this cohort of patients thus far, even though several patients have been followed-up for more than a decade, write the investigators in Molecular Therapy.

They continue: “Monitoring of this cohort is ongoing and will be incorporated into a registry for these and future patients, planned in agreement with pharmacovigilance guidelines for [gene therapy] products.

“Such a registry is vital to establish the long-term safety of [gene therapy] for the treatment of patients with ADA-SCID and to allow accurate comparisons of this new treatment with SCT, ERT, and the emerging class of lentiviral-based [gene therapy] vectors.”

The team plans to make the long-term safety and efficacy data from the registry publicly available as the cohort matures.


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