Can Gene Therapy Treat ‘The Royal Disease’
Last year, the US Food and Drug Administration approved Roctavian, an adeno-associated virus (AAV) vector-based gene therapy for the treatment of adults with severe haemophilia A which is a potentially serious bleeding disorder. This stands as the first gene therapy for adults with severe haemophilia A, also recommended by the European Medicines Agency. With World Haemophilia Day celebrated on April
17, we pause and reflect on whether gene therapy can be regarded as the most effective form of treatment for this condition or not.
Studies have revealed that gene therapy for haemophilia (referred to as “the royal disease”) in its current form is not qualified as a cure for haemophilia, though it can certainly relieve the burden of treatment from patients for several years at least. There is another less common form of haemophilia called haemophilia B. However, haemophilia A is 5 times more prevalent than haemophilia B and also has a 5 times greater need for gene therapy.
According to the World Federation of Haemophilia (WFH), there are an estimated 815,100 cases of haemophilia worldwide, of which only 347,026 are diagnosed, with 276,900 cases being severe haemophilia.
People with haemophilia have always been considered good candidates for gene therapy because their clinical manifestations are due to a lack of a single protein that circulates in minute amounts in the bloodstream. For instance, severe haemophilia A cases account for less than 1 per cent of FVIII in the blood, and thus the patients experience bleeding following an injury and may have frequent spontaneous bleeding episodes. On the other hand, people with mild haemophilia carry 6 to 49 per cent of FVIII in the blood and normal levels of FVIII range from 50 to 150 per cent.
The effectiveness of gene therapy can be considered from two perspectives: first, the expression level of the desired gene must be high enough to cure or at least alleviate the disease; and second, the expression should be sustained for a long period, ideally, for a lifetime.
The genetic defect causing haemophilia is very simple in comparison with some genetic diseases that may be caused by multiple gene mutations or one of many possible mutations. Further, the effect of gene therapy for haemophilia can be easily measured by a simple blood test of factor VIII level, which is already clinically available.
According to research, a major obstacle to gene therapy of haemophilia A is that the cDNA of FVIII is about 7 kb which is much longer than the capacity of an AAV vector, commonly used for gene therapy applications. The AAV-based approach also provides challenges such as pre-existing neutralising antibodies (NAb) due to natural AAV infections as well as immune reactions toward gene-transferred cells.
As alternatives, lentiviral vectors or genetic editing are already successful in the treatment of other genetic diseases or animal models of haemophilia but none has been tested for haemophilia with clinical trials.
In the Indian context, a major development was recently announced by Dr Jitendra Singh, the Science and Technology Minister, that researchers at Christian Medical College (CMC) Vellore have conducted the first human clinical trial of gene therapy for haemophilia A, also called the factor (F) VIII deficiency, or the classic haemophilia.
The trials involved deploying a novel technology of using a lentiviral vector to express an FVIII transgene in the patient’s haematopoietic stem cell which will then express FVIII from specific differentiated blood cells. While the team is hopeful that manufacturing of this vector will commence soon in India to proceed with further clinical trials, the necessary infrastructure and capacity will pose real challenges to its successful implementation in the country. Nonetheless, gene therapy will continue to evolve and improve to drive the hope of a haemophilia-free world in the future.