How can gene therapy cure haemophilia A? | Explained

Among the emerging approaches to fix diseases such as haemophilia, which is due to a defective gene on the X chromosome, is gene therapy.
| Photo Credit: Getty Images

The story so far: Medical researchers at the Christian Medical College, Vellore have reported successfully applying gene-therapy to treat severe haemophilia A, a rare, hereditary condition that results from a faulty gene which triggers severe, spontaneous and fatal bleeding episodes.

What is the usual treatment?

The primary approach to treating haemophilia is called replacement therapy. As the disease is a condition resulting from low levels of clotting factor — necessary to prevent bleeding — replacement therapy involves slowly dripping, or injecting into a vein, concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B). Clotting-factor concentrates can be derived and manufactured from human blood, which must be properly tested and screened to prevent the spread of diseases, such as hepatitis. It is also possible to use clotting-factor concentrates that aren’t made from human blood reducing, the albeit very small risk, of contracting diseases from injecting blood. These are called recombinant clotting factors and can be easily stored, mixed, and used at home. Haemophiliacs can regularly inoculate themselves with replacement therapy to prevent bleeding, and is meant to protect against unexpected bleeding episodes. Among the challenges with clotting factors is that the body’s own antibodies can destroy the clotting factor before it has a chance to work and defeats the whole idea of replacement therapy. Other forms of treatment include desmopressin (DDAVP), a man-made hormone used to treat people who have mild haemophilia A. DDAVP isn’t used to treat haemophilia B or severe haemophilia A. This hormone increases the level of clotting factor in the blood.

What is gene therapy in haemophilia?

Among the emerging approaches to fix diseases such as haemophilia, which is due to a defective gene on the X chromosome, is gene therapy. Here copies of a ‘corrected’ gene are introduced into the cells of a patient, the idea being that this would result — in the case of haemophilia — normal expression of the necessary clotting factor. So far there is only one U.S. Food And Drug Administration-approved gene therapy for haemophilia. Called Roctavian, it is an adeno-associated virus vector-based gene therapy and approved only in 2023 for treating adults with severe haemophilia A, and that too only for those without pre-existing antibodies to adeno-associated virus. Roctavian consists of a viral vector carrying the necessary gene for clotting Factor VIII. The gene is expressed in the liver to increase blood levels of FVIII and reduce the risk of uncontrolled bleeding. The effectiveness of the treatment was established based on results from 112 patients followed up for at least three years after Roctavian treatment. Following the infusion, the mean, annualised bleeding rate decreased from 5.4 bleeds per year at baseline to 2.6 bleeds per year. The majority of patients who received Roctavian also got corticosteroids to suppress the immune system for the gene therapy to be effective and safe. Treatment response to Roctavian may decrease over time.

How was the Vellore trial different?

The main difference in this approach is the use of a lentivirus as the vector, instead of an adenovirus. Because adenovirus infections are fairly common in people, the chances of having antibodies are fairly high and this could actually be counter-productive to those using treatments such as Roctavian. Lentivirus infections being less common, it is expected that fewer people will have antibiodies to them, making them more effective in treatment. Further the Indian approach relies on gene transfer into adult stem cells with the lentiviral vector that integrates with the body’s cells instead of in vivo transfer to a hepatocyte, or a liver cell, through a non-integrating AAV vector. The advantage of this approach is expected to be a reliable, life-long production of the clotting factor in necessary quantities without side-effects. Though tested in only five patients in Vellore, none of them reported bleeding episodes over an average follow-up period of 14 months.

Is haemophilia treatment affordable?

A March 2024 research study in the journal Heliyon, estimates the per-patient cost of treating a haemophiliac in India to be $3,00,000 over a 10-year period. Based on various estimates, there may be about 1,00,000 haemophiliacs with type A and type B conditions, with the former being more common. This is the reason why treatments can be expensive. Roctavian is also not cheap and costs nearly $2 million. Whether the gene-therapy product tested in the India will be affordable remains to be seen, though that is the hope. “It is too early to talk about costs but in principle it will need to be something that will make sense in the Indian healthcare system,” Dr. Alok Srivastava, Head, Haematology Research Unit, St John’s Research Institute, Bangalore, told The Hindu. He led the trial at Vellore.