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Having gene therapy

How will I have gene therapy for haemophilia?

AAV vector gene therapy infusion process

Gene therapy is often given in a single infusion (drip or slow injection) of fluid that contains the AAV vector with the functional gene. If you are having gene therapy, you will visit the clinic administering your clinical trial and have the infusion into a vein.

When the AAV vector is in your bloodstream, it will travel to your liver. There it will bind to liver cells. The vector DNA will enter the nucleus of the cell. Then the functional gene in the DNA will give your body instructions to produce factor VIII or factor IX proteins that work so that your blood clotting will improve.

Your body will take several months to increase the amount of functional factor VIII or factor IX in your blood and stabilise.

How effective is gene therapy?

Gene therapy for haemophilia has been studied in humans for more than 20 years. Early clinical trials in haemophilia were not successful but addressed many technical problems that needed to be overcome.

More recent clinical trials with AAV vectors have only involved small numbers of people. To see what would improve results the trials tested a range of doses and different variants of functional factor, such as the factor IX Padua variant, which occurs naturally. This variant has enhanced factor IX activity.

The AAV vector trials for haemophilia A and haemophilia B were testing to see what sustained results could be seen 12 months after the infusion. The most successful trials had results showing that at this point:

  • most participants with severe haemophilia (less than 1% of normal factor activity) had increased their factor activity levels to the mild haemophilia range (5-40%)
  • some had increased their factor activity levels to the normal range (more than 40%)
  • most had been able to stop prophylaxis
  • nearly all had few if any bleeds in the last 12 months.

Many questions remain, including how long this effect will last and how long to monitor for safety. These clinical trials have been following up the people who had gene therapy for between 1 and 8 years.

Current clinical trials in Australia may be testing these or different treatment approaches. If you are considering taking part in a clinical trial for gene therapy, it is important to find out what it is testing and what the previous trial results have shown. 

What about immunity to AAV?

A challenge with using AAV to deliver the gene is that it is a virus and people’s immune systems may attack it and destroy it.  Many strains of the virus AAV already exist in the community and many people have already been exposed to it at some stage during their life, although they would not know because it does not cause illness in humans. If they have been exposed to AAV, their body will have produced antibodies and immune cells to make them immune to AAV. The antibodies will recognise AAV and attack the AAV capsid/shell, so that the treatment doesn’t work.

Most current clinical trials exclude people who have pre-existing immunity to AAV. However, researchers are looking at ways to overcome this, for example, with higher doses or by engineering the AAV capsid so that it can hide from the immune response. Some new international clinical trials are testing this.

What are the side-effects of gene therapy?

A common side-effect of gene therapy with the AVV vector is an immune reaction where ALT (alanine transaminase) levels in the liver are raised. There are not usually other immune-related symptoms and the reaction is treated with corticosteroids, which may also have side -effects.

Other side-effects have included:

  • lethargy, tiredness
  • anaemia (low levels of red blood cells)
  • back pain.

How safe is gene therapy?

Much of the research into gene therapy is relatively recent and there will need to be many more years of clinical trial follow-up to have more certainty about the long-term effects and safety.

As yet no major safety problems have been identified with gene therapy using AAV vectors. They are unlikely to affect a person’s genome (the complete set of DNA present in your cells that define how your body works) or to cause cancer. Although DNA from AAV can be found in body fluids for up to a year after infusion, they do not appear to be infectious. Nevertheless, to be absolutely sure, the current clinical trials are monitoring this and asking participants to take precautions to make sure no pregnancies occur in the 12 months following the infusion.
Researchers are also concerned to find out if any participants have a response where their factor activity levels raise to the higher end of normal, eg over 100% of normal, and if this will create a risk of thrombosis. Where possible they are aiming to avoid a response that is too high.

Date last reviewed: 12 October 2019

Important Note: This information was developed by Haemophilia Foundation Australia for education and information purposes only and does not replace advice from a treating health professional. Always see your health care provider for assessment and advice about your individual health before taking action or relying on published information. This information may be printed or photocopied for educational purposes.

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