Gene Therapy for Bleeding Disorders

This set of flashcards covers key concepts from Dr. Ellie Karampini's lecture on gene therapy for bleeding disorders, specifically targeting haemophilia A and B.

What is the biological basis for haemophilia that makes it a target for gene therapy?

Haemophilia is caused by deficiency of important plasma clotting factors: Haemophilia A (factor VIII) and Haemophilia B (factor IX), which results in reduced thrombin generation and increased bleeding risk.

What is the aim of treatment for haemophilia patients?

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

What are the major challenges of gene therapy for haemophilia A?

The size of the FVIII gene exceeds the packaging capabilities of AAV vectors, and FVIII expression is very limited compared to FIX.

What is Etranacogene dezaparvovec?

A gene therapy treatment for haemophilia B, showing high, durable FIX activity and a favorable safety profile.

What eligibility criteria must be met for gene therapy in haemophilia patients?

Patients must be 18+, have no history of inhibitors, no serious liver disease, and no pre-existing antibodies to the AAV vector.

What significant risk is associated with the use of adeno-associated virus (AAV) vectors in gene therapy?

There is a high immunogenic response to the AAV capsid, which can result in hepatotoxicity.

What major factor makes gene therapy for haemophilia A promising despite its limitations?

Both haemophilia A and B are monogenic disorders, which do not require restoration of full normal levels to be effective.

What potential long-term safety concern exists regarding the integration of gene therapy vectors?

Integration of the vector into the person's DNA could increase the theoretical risk of cancer if it occurs in genes linked to cancer.

What has been a historical treatment for haemophilia before gene therapy?

Administration of plasma-derived coagulation factors, which was halted due to the HIV crisis.

What are the different types of haematological rates seen in haemophilia patients depending on severity?

Severe haemophilia (factor activity <1%) leads to spontaneous bleeding, while mild haemophilia (factor activity between 1-5%) leads to bleeding usually after trauma or surgery.