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Deciphering conundrums of adeno-associated virus liver-directed gene therapy: focus on hemophilia
Glenn F Pierce1, Sylvia Fong2, Brian R Long2
1World Federation of Hemophilia, Montreal, Quebec, Canada.
Abstract:
Adeno-associated virus gene therapy has been the subject of intensive investigation for monogenic disease gene addition therapy for more than 25 years, yet few therapies have been approved by regulatory agencies. Most have not progressed beyond phase 1/2 due to toxicity, lack of efficacy, or both. The liver is a natural target for adeno-associated virus since most serotypes have a high degree of tropism for hepatocytes due to cell surface receptors for the virus and the unique liver sinusoidal geometry facilitating high volumes of blood contact with hepatocyte cell surfaces. Recessive monogenic diseases such as hemophilia represent promising targets since the defective proteins are often synthesized in the liver and secreted into the circulation, making them easy to measure, and many do not require precise regulation. Yet, despite initiation of many disease-specific clinical trials, therapeutic windows are often nonexistent, resulting in excess toxicity and insufficient efficacy. Iterative progress built on these attempts is best illustrated by hemophilia, with the first regulatory approvals for factor IX and factor VIII gene therapies eventually achieved 25 years after the first gene therapy studies in humans. Although successful gene transfer may result in the production of sufficient transgenic protein to modify the disease, many emerging questions on durability, predictability, reliability, and variability of response have not been answered. The underlying biology accounting for these heterogeneous responses and the interplay between host and virus is the subject of intense investigation and the subject of this review.
Insights
Adeno-associated virus (AAV) gene therapy shows promise for monogenic diseases like hemophilia, but challenges in efficacy and toxicity persist. Ongoing research focuses on understanding host-virus interactions to improve AAV gene therapy outcomes.
Area of Science:
- Gene Therapy
- Virology
- Hepatology
Background:
- Adeno-associated virus (AAV) gene therapy has been investigated for over 25 years for monogenic diseases, with limited regulatory approvals due to toxicity and efficacy issues.
- The liver is a primary target for AAV due to hepatocyte tropism and liver sinusoidal geometry, making it suitable for diseases like hemophilia where proteins are secreted.
- Despite numerous clinical trials, challenges remain in achieving therapeutic windows, leading to variable efficacy and toxicity.
Purpose of the Study:
- To review the progress and challenges in adeno-associated virus gene therapy for monogenic diseases.
- To highlight the liver as a key target organ and hemophilia as a model disease.
- To discuss the critical unanswered questions regarding durability, predictability, reliability, and response variability in AAV gene therapy.
Main Methods:
- Review of existing literature and clinical trial data on adeno-associated virus gene therapy.
- Analysis of factors influencing AAV tropism and efficacy in the liver.
- Examination of host-virus interactions and their impact on therapeutic outcomes.
Main Results:
- Few AAV gene therapies have gained regulatory approval, often due to toxicity or lack of efficacy in early-phase trials.
- Hemophilia gene therapy has seen iterative progress, culminating in recent regulatory approvals.
- Significant questions persist regarding the long-term durability, predictability, reliability, and variability of patient responses to AAV gene therapy.
Conclusions:
- Adeno-associated virus gene therapy holds potential for monogenic diseases, but overcoming toxicity and efficacy hurdles is crucial.
- Understanding the complex interplay between the host and the virus is essential for optimizing AAV gene therapy.
- Further research is needed to address the heterogeneity of responses and ensure consistent, reliable therapeutic outcomes.
