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What is investigational gene therapy meant to do?

The purpose of this site is to provide information to patients and caregivers about the field of gene therapy and how it is being investigated for use in haemophilia.

Step by step

The overall goal of investigational gene therapy is to deliver a functional gene to a specific, or target, cell.

Think of the functional gene as the instruction manual that tells the body how to make a desired protein.

Once a functional gene is created, there must be a way to deliver it to the right address, or target cells. The functional gene can be inserted into a viral-based shell, creating a delivery package known as a vector.

The vector’s sole purpose is to deliver the functional gene to the correct target cell type — just like an envelope that ensures the instruction manual gets to the right address. The envelope (vector) is then placed into the postbox (body) and mailed to the correct address (target cell type) to deliver the instruction manual (functional gene).

Vectors are chosen because they have an affinity, or preference, for a specific cell type or types, allowing the functional gene to get to the right place. They’re sort of like a pre-addressed envelope that can only be sent to a particular address.

Goals for AAV gene therapy research in haemophilia

The primary research goal is to evaluate the safety and effectiveness of gene therapy intended to deliver a functional gene. Secondary goals include determining dosage of a potential gene therapy (e.g. how many times it is administered, and the appropriate dose needed to balance benefits and risks).

Investigational gene therapy for haemophilia is designed to add a functional copy of the factor VIII or factor IX gene to the cell’s command centre (nucleus). If transferred successfully, the functional gene is intended to provide the correct instructions for the cell to make factor VIII or factor IX clotting protein.

In this case, a virus is used as the delivery vehicle or vector. First the viral genetic information is removed. The new DNA (functional gene) is placed inside the viral-based shell, which can carry the new gene into the body. The vector is delivered into the body via intravenous (IV) infusion into the blood.

The vector used in haemophilia gene therapy research has a preference to travel to liver cells (hepatocytes).

Modified viruses as vectors

In gene therapy research, modified viruses are the most commonly used method for the delivery of genetic material. Over millions of years, viruses evolved to be very good at placing genetic information into other cells. They also have a natural ability to target specific cell types in the body.

To modify a virus for use in gene therapy research, its own genetic information is replaced by the functional gene. It’s now no longer a virus, but a vector, or transporter. Vectors are modified to be non-pathogenic, meaning they cannot reproduce the virus and cause disease.

Creating a vector

Adeno-associated virus (AAV) is commonly used as a vector in gene therapy research overall and specifically in gene therapy research for haemophilia.

There are a few reasons why AAV is used:

  • It is not known to cause human disease.
  • It has relatively low pre-existing antibodies (immunogenicity). This means there is a lower chance a patient would have previously been exposed to it. The immune system would, therefore, not recognise it and not attempt to destroy the vector before it had its chance to reach the target cells.
  • It can fit the functional factor gene inside.
  • There are a variety of naturally occurring versions of AAV, which prefer, or have an affinity for, different cell types (tropism).