Lecture 7 - Gene therapy for bleeding disorders

What are the two types of haemophilia associated with specific factor deficiencies?

Haemophilia A (factor VIII deficiency) and Haemophilia B (factor IX deficiency).

What is the aim of treatment for haemophilia patients?

To increase factor levels above 10% of normal to reduce the risk of spontaneous bleeding.

Why are haemophilia A and B considered good targets for gene therapy?

They are monogenic disorders, do not require restoration of factor levels to 100% for effectiveness, and have liver-targeted gene delivery.

What is a major drawback of using adeno-associated virus (AAV) vectors in gene therapy?

High immunogenic response to their capsid, which may lead to hepatotoxicity.

Who is generally eligible for gene therapy for haemophilia?

Individuals aged 18+, with no history of inhibitors, serious liver disease, or pre-existing antibodies to the AAV vector.

What is the main challenge in gene therapy for Haemophilia A compared to Haemophilia B?

The size of the FVIII gene is larger than that of FIX, making it difficult to package into AAV vectors.

What is the FIX ‘Padua’ variant and its significance?

A FIX variant with 10-15x higher activity than wild type FIX, identified in a child with thrombophilia.

What are some early problems seen with gene therapy approaches for haemophilia B?

Durable but low FIX expression or high but short-lived expression.

What has been identified as a common safety concern in gene therapy?

Short-term liver inflammation, which may require the use of steroids.

How long may factor expression from gene therapy last for FVIII and FIX?

FVIII expression may last for 5-8 years, whereas FIX expression may last for up to 10 years.

What are two challenges associated with the cost of gene therapy?

High initial treatment costs and accessibility for people in developing countries.

What is a potential long-term safety concern with gene therapy?

Integration of the gene therapy vector into the individual’s DNA, which could increase the theoretical risk of cancer.

Why is the measurement of factor levels post-gene therapy important?

To assess the success of the therapy and the durability of factor expression in preventing bleeds.

What happened to haemostatic therapies for haemophilia in the 1980s?

Administration of plasma-derived factors was stopped due to the risk of HIV transmission.

What are some current approaches to haemophilia gene therapy?

Utilization of hepatocyte-directed adeno-associated virus (AAV) vectors expressing factors, like factor IX.