A "very basic" type of gene therapy could potentially cure hemophilia, but a major hurdle has been the lack of an effective mode of delivery. Recent strides in using adeno-associated virus (AAV) vectors are changing that, and Glenn Pierce, MD, World Federation of Hemophilia Vice President, Medical, predicts approvals in the next 12-18 months. Dr. Pierce shared his personal experience with hemophilia and discussed his and others' ongoing research on the use of AAV-mediated gene therapy with host David Henry, MD, in this episode. Hemophilia and AAV gene therapy key points: Hemophilia is caused by a monogenic defect and could, theoretically, be cured by gene replacement or augmentation, says Dr. Pierce, who notes that "it sounds disarmingly simple, but behind that simplicity is a very complex procedure." The approach uses "gene addition," which is a basic gene therapy involving the addition of a normal gene to the variant in an individual. This ultimately corrects the clotting factor deficiency. The complexity is in getting the normal gene into the body where it can have the intended therapeutic effect. After more than 20 years of working to overcome that barrier, Dr. Pierce and others are finding success with using AAVs. The approach has some similarities to that used in developing the mRNA COVID-19 vaccines but requires the use of DNA established within the virus (rather than mRNA) to provide a more stable effect. Questions about how long it will last are currently being investigated. Multiple phase 3 trials are underway or completed. Data from two of those have been released in recent months, and the results are very encouraging: "It's a remarkable achievement – many patients are doing well and, for all intents and purposes, could be considered free of [hemophilia]," Dr. Pierce says, adding that he would "potentially … use the 'C word' – cured – for at least a period of time." The therapy is generally well tolerated. Efforts are ongoing to identify the best ways to proactively and reactively use prednisone to manage side effects such as mild increases in transaminase levels. To date, the risk-benefit profile appears reasonable for patients with clotting factor IX deficiency, and it is likely that the therapy in that setting "will march toward the regulatory process to determine if it's safe and effective for approval," he said. Responses in those with clotting factor VIII deficiency have been more variable, with some patients requiring long-term prednisone use, which is problematic. More information is needed about this, but investigation is ongoing, he said. Registries are available and many companies are involved in clinical trials. Clinicians and patients can look for information at clinicaltrials.gov, wfh.org (which publishes trial results and conducts workshops and meetings), and at the US National Hemophilia Foundation (Hemophilia.org) and the Society of Thrombosis and Hemostasis (ISTH.org). Show notes written by Sharon Worcester, MA, a reporter for MDedge and Medscape. Disclosures Dr. Henry has no relevant disclosures. Dr. Pierce disclosed relationships with Ambys Medicines, BioMarin, BridgeBio, CRISPR Therapeutics, Decibel Therapeutics, Frontera, Geneception, Generation Bio, Novo Nordisk, Pfizer, Regeneron, Third Rock Ventures, Voyager Therapeutics, Global Blood Therapeutics, VarmX SAB, the National Hemophilia Foundation Medical and Scientific Advisory Council, and the World Federation of Hemophilia. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

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