Gene therapy for haemophilia A successfully halts bleeds

A new one-time gene therapy has prevented bleeding episodes in haemophilia A patients in an investigational study carried out in India.

Haemophilia A is an X-linked bleeding disorder that is caused by mutations in the F8 gene. This leads to inactivation of the protein it encodes, factor VIII, which is essential in blood clotting. Affected patients experience episodes of excessive and uncontrolled bleeding. Currently, the only gene therapy approved by the US Food and Drug Administration (FDA) does not prevent all bleeding episodes and patients are required to take immunosuppressants due to the adeno-associated virus (AAV) vector used (see BioNews 1197). In this small-scale study of five patients, the new gene therapy completely stopped bleeding episodes for a follow-up period ranging from nine to 27 months, with no adverse events reported.

'Five participants, 22 to 41 years of age at study recruitment, received the investigational gene-therapy product,' wrote researchers who carried out the trial at the Christian Medical College, Vellore, India, in the New England Journal of Medicine. 'The annualised bleeding rate was zero for all five participants over a cumulative follow-up of 81 months.'

The researchers fused haematopoietic stem cells, extracted from the patients, with the F8 gene using a lentiviral vector. These were then administered to the patients.

Lentiviral vectors are derived from HIV and are highly efficient at integrating transgenes into the genome. The lentiviral vector used in the study is self-inactivating, which means it is 'switched off' after delivering the cargo.

After initial delivery of the gene therapy to two patients, the researchers modified the delivery with an enhancer. This improved the delivery of the vector so that only a single dose needed to be delivered to the remaining three patients, with the same improvements in uncontrolled bleeding.

This novel gene therapy overcomes several challenges associated with currently available therapies. For example, the FDA approved gene therapy's effectiveness may decrease over time, and it cannot be administered multiple times or to patients with detectable antibodies against the AAV, as this could trigger a dangerous immune response.

'In a groundbreaking first-in-human, single-centre study... [Dr Alok] Srivastava and colleagues report on the successful autologous transplantation of CD34+ haematopoietic stem cells transduced with a lentiviral vector carrying a new F8 transgene,' wrote Professor Johnny Mahlangu, who was not involved in the study, in an editorial in the New England Journal of Medicine.

Despite the success of the trial, several concerns remain. High factor VIII expression could pose a risk of thrombosis, the formation of blood clots inside blood vessels. In the study, the factor VIII levels in the patients remained in the moderate range, however this needs to be replicated to confirm that factor VIII expression remains stable.

Professor Mahlangu continued: 'Only time will tell whether this strategy... is successful. Because this study involved a limited number of participants and a short duration of follow-up, whether F8 gene delivery through a lentiviral vector is a viable alternative to AAV-mediated F8 gene therapy remains unclear.'