After decades of investigation, gene therapy has received regulatory approval to treat hemophilia. However, since gene therapy investigations were initially conceived, other avenues of treatment have revolutionized the care of hemophilia. Emergent data is showing that gene therapy may not be as beneficial as hoped and more toxic than planned. At a minimum, a reassessment of risk/benefit estimate of gene therapy for hemophilia is needed.
The past 2–3 decades have seen tremendous advances in the treatment of hemophilia. Unlike many other genetic diseases, hemophilia patients can expect a near normal lifespan with controllable morbidities. The burden of treatment remains but is becoming lighter. Thus, any new treatments are tasked with demonstrating superior efficacy (reduced bleeding risk, medication administration, morbidity, mortality, costs, etc.) to current and near future treatments with little to no added risk. In other words, gene therapy must have “flawlessly safety” (63). Gene therapy for hemophilia using rAAV does not appear to meet those requirements. Long term data with rAAV gene therapy is lacking. Although indirect evidence points toward the possibility of normalizing the lifespan of some hemophilia patients, that remains to be proven. Hemophilia gene therapy may reduce the risk of hemophilic arthropathy that develops during adulthood. Because rAAV gene therapy will not be given to children, it will have no impact on joint disease that develops prior to adulthood. The lifetime risk of joint disease in people in the general population is well over 50% (64). Thus, even if it is shown that gene therapy reduces the risk of hemophilic arthropathy, large numbers of hemophilia patients will still develop joint disease. The inconvenience of monthly subcutaneous injections currently or soon to be available for hemophilia remains. However, in comparison to most chronic diseases in which daily administration of medication is needed, the burden of hemophilia treatment is no longer onerous. Hence, the benefits of hemophilia gene therapy with rAAV are marginal. It is often claimed that the risk of hemophilia gene therapy with rAAV is “low,” but what exactly is meant by “low” is not defined (2, 35, 62). If the latency for development of HCC with rAAV is like that of hepatitis B and C, we will not know the true risk for HCC following rAAV gene therapy for several decades. Clinical trials are not powered to detect rare complications. Therefore, the risk of hemophilia gene therapy with rAAV cannot currently be quantified. It is not zero and is potentially catastrophic. In addition, a proper epidemiological investigation of the growing number of reports of cancer following rAAV gene therapy for hemophilia is needed. Also needed are investigations of DRG toxicities in hemophilia patients following rAAV gene therapy. The reason(s) for falling factor VIII activity following rAAV gene therapy remain unresolved and need clarification before rAAV is widely used for this disorder. Gene therapy for hemophilia was first proposed when the complications of this disorder were substantial. In the decades it has taken for rAAV gene therapy to become successful, gains in the standard of care have become revolutionary. Any new treatment that is “low” risk may be too high of a risk for hemophilia patients. All new treatment requires an assessment of risks and benefits. Despite the rare fatal risks due to rAAV for SMA, the benefits still outweigh the risks for this disorder. Based on the data presented here, that does not seem to be the case for hemophilia gene therapy with rAAV.
Font: Front. Med. 10:1256919
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Title
Emergent data influences the risk/benefit assessment of hemophilia gene therapy using recombinant adeno-associated virus
Author: John Puetz