Gene therapy – are we ready now?

Abstract

Introduction:Haemophilia therapy has evolved from rudimentary transfusion-based approaches to an unprecedented level of innovation with glimmers of functional cure brought by gene therapy. After decades of misfires, gene therapy has normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several clinical programmes testing adeno-associated viral (AAV) vector gene therapy are approaching completion with imminent regulatory approvals.Discussion: Phase 3 studies along with multiyear follow-up in earlier phase investigations raised questions about efficacy as well as short-and long-term safety, prompting a reappraisal of AAV vector gene therapy. Liver toxicities, albeit mostly low-grade, occur in the first year in at least some individuals in all haemophilia A and B trials and are poorly understood. Extreme variability and unpredictability of outcome, as well as a slow decline in factor expression (seemingly unique to FVIII gene therapy), are vexing because immune responses to AAV vectors preclude repeat dosing, which could increase suboptimal or restore declining expression, while overexpression may result in phenotoxicity. The long-term safety will need lifelong monitoring because AAV vectors, contrary to conventional wisdom, integrate into chromosomes at the rate that calls for vigilance.Conclusions: AAV transduction and transgene expression engage the host immune system, cellular DNA processing, transcription and translation machineries in ways that have been only cursorily studied in the clinic. Delineating those mechanisms will be key to finding mitigants and solutions to the remaining problems, and including individuals who cannot avail of gene therapy at this time.

Hepatitis after gene therapy, what are the possible causes?

“…8 Rises in ALT are generally transient-1 to 3 times the upper limit of normal (ULN) but levels have been seen up to 20 times the ULN or noted to persist over months or years. 2 As many as 86% of patients developed elevations in their liver enzymes, particularly ALT at 7-14 weeks post-drug administration in one of the pivotal clinical trials for haemophilia A. 9 The median time to the first ALT elevation was 8 weeks, with a median duration of 15 days.…”

“…The instances of elevations in aminotransferases vary for FVIII and FIX studies, occurring more commonly in haemophilia A and with a severity that appears to be dose-dependent. 2 Trials for haemophilia B use AAV vectors that express FIX with a gain of function Padua mutation, which codes for FIX protein that has increased activity, this allows a lower dose to be given to haemophilia B patients and may, perhaps, mitigate the ALT elevations. 11 Transgene expression for FIX is more durable and stable over time which may reflect the degree of liver inflammation.…”

“…However, patients studied in clinical trials underwent a vigorous pre-treatment assessment for liver health and individuals with known liver disease, active and chronic liver infections with hepatitis B and C and patients with HIV on hepatotoxic medications were not recruited. 2 This criterion meant that a large proportion of haemophilia patients were excluded as those treated with plasma-derived factor products in 1980s may have iatrogenically acquired these conditions from donated blood products. 3 Hence, although the current safety data suggests that the AAV associated hepatitis in patients with haemophilia is clinically unimportant, care will be required as the treatments are increasingly used in patients with pre-existing liver damage.…”

“…The transgene containing genetic information for the production of FVIII and FIX is transferred to the hepatocytes; here it enters the cytoplasm and then the cell's nucleus. 2 The vector capsid uncoats and the genetic material contained forms circular episomal vector DNA in the hepatocyte nucleus. 3 The genetic material then undergoes the complex process of transcription and translation to produce the factor protein required.…”

“…3 The genetic material then undergoes the complex process of transcription and translation to produce the factor protein required. 2…”