A breakthrough has been achieved in India in treating 'Haemophilia A' cases, as researchers have successfully carried out the lentiviral gene therapy to treat this genetic blood disorder. The development is significant as India bears the world’s second-largest burden of haemophilia, with an estimated caseload of around 136,000 individuals.
What is haemophilia
Haemophilia is a genetic bleeding disorder in which the body's clotting ability is impacted, resulting in prolonged bleeding in case of injury or even without any reason. It is a serious condition that is more common in males. There are two types of Haemophilia, A and B. The difference between the two is determined by the deficiency of a specific clotting factor in an individual.
While Haemophilia A is caused by a deficiency of clotting Factor VIII, Haemophilia B denotes a deficiency of Factor IX. These factors are a group of proteins that play a vital role in blood clotting.
For instance, Factor VIII, the lack of which causes Haemophilia A, is a protein known as antihemophilic factor. This condition accounts for approximately 80% of all haemophilia cases and affects about 1 in 5,000 male births globally. As such, the lentiviral gene therapy approach is a breakthrough and transformative strategy for treating haemophilia A bleeding disorder.
What is lentiviral gene therapy?
In lentiviral-based gene therapy, lentiviruses are used to add a healthy gene into a person's cells to treat the disease. For treating Haemophilia A, the approach uses the patient’s hematopoietic stem and progenitor cells (HSPCs) transduced with a lineage-restricted lentiviral vector to encode a bioengineered Factor VIII gene.
This is a novel approach where a one-time infusion of genetically modified hematopoietic stem cells (HSCs) can cure this genetic bleeding disorder. In lay language, hematopoietic stem cells are immature mother cells that give rise to all types of cells in our blood. They mainly reside in our bone marrow and can be mobilised to peripheral blood by using certain safe drugs. Hematopoiesis is a term derived from Greek words haima (blood) and poiēsis (to produce something).
The first-in-human Phase 1 clinical trial using a lentiviral vector (LV)-based gene therapy approach for treating haemophilia A was successfully conducted with five patients, and no major adverse events were reported. All patients remained free from bleeding episodes post-treatment.
Where was this therapy developed?
Lentiviral gene therapy approach was developed through a collaboration between the Centre for Stem Cell Research (CSCR), a unit of the Bangalore-based iBRIC–Institute for Stem Cell Science and Regenerative Medicine (inStem); Department of Biotechnology, Ministry of Science and Technology, Government of India; Christian Medical College (CMC) Vellore, and Emory University.
The lentivirus-based gene therapy product underwent development of robust manufacturing procedures for genetic modification of hematopoietic stem cells from haemophilia A patients, preclinical testing, and received regulatory approval to conduct a Phase 1 clinical trial.
The final drug product was manufactured under the Good Manufacturing Practices (GMP) facility at the CSCR, CMC campus, Vellore. The clinical trial was conducted at the Department of Haematology, CMC, Vellore, and supported by the Department of Biotechnology, Ministry of Science and Technology, GOI.
Current treatment for Haemophilia A
The current treatment for Haemophilia A involves frequent infusions of FVIII protein. Effective gene therapy could normalise FVIII levels and provide a lifelong cure. Gene therapy for haemophilia has been attempted for over two decades with an adeno-associated virus (AAV) based approach. Recently, Roctavian - an AAV5-based therapy was approved by the FDA.
Lentiviral-based gene therapy clinical trial
In this novel approach, hematopoietic stem cells (HSCs) are genetically modified using a lentiviral vector (CD68-ET3-LV) to express functional FVIII protein. The vector carries a specially engineered FVIII gene designed to produce high levels of clotting FVIII. When these modified HSCs develop into monocytes (a type of White Blood Cell), the CD68 promoter switch on the FVIII transgene, allowing the monocytes to produce the FVIII protein needed to treat haemophilia A and making the patient free from repeated injections of Factor VIII.
Researchers explain how the idea turned into a reality
ETV representative Anubha Jain discussed in detail the first-in-human clinical trial in an exclusive interview with Dr Aby Abraham, a lead clinician and Head of Department of Haematology at CMC Vellore, and Dr Gurbind Singh, Scientist and Head of GMP facility at Centre for Stem Cell Research.
Asked where the idea originated to cure the disease through Gene therapy, Dr Abraham noted that while the concept of gene therapy to treat monogenic disorder has been there for many decades, its adoption was delayed due to the non-availability of safe and efficient gene therapy vectors to deliver the therapeutic gene.
Also, there were existing treatments to manage the haemophilia disease, including protein concentrate, recombinant factors and monoclonal antibodies, but they need to be infused regularly. Therefore, for clinicians, scientists and patients living with Haemophilia, a deeper question persists: Why should they remain dependent on lifelong therapy? Can they ever be truly free of the infusion and disease? These concerns have fuelled the search for curative approaches that are lifelong.
While answering why the trial is the first in human study, Dr Singh noted that lentivirus-based gene therapies already exist for diseases like sickle cell anaemia and beta thalassemia, where the normal beta-globin gene is added to HSC for curing these diseases.
These therapies, developed by Bluebird Bio, are approved by the US FDA with product name- Lyfgenia. While the lentiviral approach has been used for years in treating immunodeficiency disorders, such as severe combined immunodeficiency (SCID), it has never been applied to haemophilia. This makes the gene therapy trial conducted at CMC Vellore, using a product manufactured at the CSCR, the first lentivirus-based trial for haemophilia A globally, a true first-in-human study.
Asked why a lentiviral vector platform is preferred over an AAV-based approach for treating Haemophilia A, Dr Singh highlighted the limitations of AAV-based gene therapy for haemophilia.
AAV-based therapy, he said, will not be useful to many patients who have pre-existing neutralising antibodies against various AAV serotypes. These antibodies block the infused AAV vector before it reaches the target cells to deliver the therapeutic gene.
Additionally, AAV delivers the gene (e.g., for Factor VIII) episomally (not integrated into the genome), making it unsuitable for paediatric patients, as their growing liver dilutes the episomal vector during cell division, he said.
“Re-dosing is also not possible due to antibody development after the first infusion. In contrast, the lentiviral approach combined with hematopoietic stem cells can offer lifelong FVIII production. This method will work for paediatric patients and can be given to patients even with anti-AAV antibodies. It also bypasses issues related to liver health, the need for immunosuppressive therapy, and transaminitis,” he said.
What were the challenges researchers faced
Talking about the unexpected findings or challenges during the trial, Dr Abraham explained that, as gene therapy was being introduced in the country for the first time, the team prioritised broad consultations with patient advocacy groups and health organisations to gauge readiness.
Through a nationwide outreach and feedback campaign, they found that patients and families, deeply affected by the disease, were the strongest advocates for access to the therapy, even if only within a study. Another major step was ensuring informed consent, and a group was assigned to speak with the patients to confirm that they fully understood the treatment and still wished to participate.
This multi-level process was essential to ensure ethical and informed participation. Scientifically, early challenges involved suboptimal factor levels, which were crucial for the therapy's success. A key breakthrough came from Dr Singh, who modified the manufacturing process with the addition of a transduction enhancer, resulting in significantly improved factor expression levels. This was instrumental in overcoming the scientific barrier and advancing the therapy’s effectiveness, he added.
Dr Singh explained that a major challenge in the lab was working with large numbers of hematopoietic stem cells (HSCs). Unlike T cells used in CAR-T cell therapy (for cancers like ALL or lymphoma), HSCs cannot multiply outside the body. For gene therapy, a patient weighing 60 kg needs at least 300 million HSCs, plus more cells for quality checks. This meant the team had to purify and modify a large number of stem cells, which also required a much higher amount of lentiviral vector than CAR-T cell therapy.
Another challenge was getting the right number of gene copies into each cell—known as vector copy number (VCN). Initially, the VCN was low, which limited the effectiveness of the treatment. To overcome this, transduction enhancers were used that increased the VCN. After this change, the next three patients who received the product with improved manufacturing protocol showed optimal Factor VIII levels.
Patient selection criteria and side effects
Discussing the patient selection criteria and side effects, Dr Abraham stated, “Paediatric patients, those with a history of Factor VIII inhibitor development, and individuals with major organ dysfunction (kidney, liver, or heart) were excluded. Inhibitors are antibodies that neutralise infused Factor VIII, making treatment ineffective."
He said that no major side effects have been observed so far. The main concern was the chemotherapy used as a conditioning regimen to clear existing bone marrow cells and make space for genetically modified stem cells.
"These stem cells then engraft and produce blood cells, including those making Factor VIII. Though chemotherapy temporarily lowers blood counts, increasing infection risk and the need for transfusions, it is a standard procedure at CMC Vellore and was well-tolerated by all patients without serious adverse events,” he said.
A game-changer
Dr Abraham said that the patients will be followed up regularly for at least five years—initially and for 15 years for long-term study. While the procedure is safe and no major problems are anticipated, consistent monitoring is essential to track factor VIII levels and any other adverse event.
Dr Abraham and Dr Singh said that this gene therapy could be a game-changer for patients in need and made available to all eligible patients in the future, but highlighted the high cost of GMP-grade lentiviral vectors and cytokines as a key barrier.
While hospitals can manage patient care with limited resources, the manufacturing component remains costly. They stressed the need for affordable, domestic production of critical raw materials and emphasised that collaborations, philanthropic and government support could accelerate access both in India and globally.
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