Conclusions
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 to current and near
future treatments with little to no added risk. In other words, gene
therapy must be “flawlessly safe.” 62 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%.63 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.2,35,61 If the latency for development of HCC
with rAAV is like that of hepatitis B and C, we won’t 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.