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Gene therapy: Shifting the paradigm for patients with hemophilia A

For many people with hemophilia A, a specific genetic defect is the underlying cause for the bleeding disorder. Gene therapy is attempting a new approach using one infusion to abolish the need for life-long regular intravenous injections.

Due to a lack of a certain blood clotting protein, people with hemophilia are constantly concerned about injuries and accidents, as even minor ones can cause major bleeding. Severely affected patients can also experience bleeding in their joints in the absence of a trauma, leading to chronic joint damage, or face life-threatening bleeding within vital organs, such as bleeding in the brain or gastrointestinal tract.


Hemophilia A, the most common form of hemophilia, affects about 320,000 people worldwide and results from a deficiency of the clotting factor “Factor VIII”.  Severity of symptoms depends on the amount of Factor VIII present. For many patients, treatment entails regular Factor VIII replacement therapy via intravenous infusions, several times a week or even daily. Injections often start in early childhood, when the patient is first diagnosed, and continue over their entire lifespan. In many cases, lack of compliance to this burdensome standard of care leads to suboptimal treatment and, hence, subsequent poor clinical outcomes. Researchers are thus aiming to relieve the burden of treatment and of the disease by developing Factor VIII gene therapies.


Expert insights: Replacing a faulty gene

Two-thirds of people with hemophilia A have inherited a malfunctioning gene in which Factor VIII is not produced at sufficient levels. Dr. Francesca Ferrante, Global Clinical Lead of Bayer’s Factor VIII gene therapy program, explains the new approach: “The intention of a gene therapy agent is to deliver intact copies of the defective Factor VIII gene into the patient’s body, to initiate the endogenous production of active Factor VIII with only one injection.” If that works appropriately, patients can start producing their own FVIII protein, restoring normal blood clotting function.


Researchers at Bayer are investigating a specific gene therapy approach using an adeno-associated virus (AAV) vector as shuttle to transport the Factor VIII gene into the body. The AAV vector is specifically designed to target liver cells, as these constitute a major production site of endogenous FVIII. In some patients, viral vectors can cause innate or adaptive immune responses. While this is not dangerous, some immune responses may lead to a decreased efficiency of gene transfer or elimination of the transduced gene over time. Dr. Ferrante explains: “Exploring novel capsid vectors for gene therapy in the hemophilia population may provide treatments for those who have immunity to other vectors.”


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Implications: No ‘one-size-fits-all’ gene therapy

Stemming from a collaboration with the US-biotech company Ultragenyx, Bayer launched a first clinical trial in the end of 2018 to investigate FVIII gene therapy in patients with severe hemophilia A. The trial is evaluating the tolerability and safety as well as FVIII activity after a one-time injection of the investigational therapy. To date, six patients have been treated with increasing doses. As Dr. Ferrante notes: “To really make a difference for patients, we want to achieve stable and close to normal expression levels of FVIII that can be sustained over a long period of time. The interim results are very encouraging but further studies are warranted to evaluate the safety and efficacy of this investigational FVIII gene therapy.”


Looking ahead: Small vector, big impact

The potential of gene therapy has been likened to giving a “new coagulation system” to hemophilia A patients who are obliged to restrict their activities, limit their lifestyle, and cope with anxiety around risks of bleeding from everyday occurrences. Looking ahead, Dr. Ferrante remarks “We are excited to advance the FVIII gene therapy further and be part of the journey to achieve a breakthrough for hemophilia patients”.