Abstract
Adeno-associated virus (AAV) vector-based gene therapy is currently the only in vivo gene therapy approved in the US and Europe. The recent tragic death of three children in a clinical trial to treat X-Linked Myotubular Myopathy by delivering myotubularin with an AAV8 vector notwithstanding, AAV remains a highly promising therapeutic gene delivery platform. But the successful use of AAV vectors to treat an increasing number of diseases also makes establishing protocols to determine therapeutically relevant titers of pre-existing anti-AAV antibodies and approaches to deplete those antibodies more urgent than ever. In this mini review, I will briefly discuss (i) our knowledge regarding the prevalence of anti-AAV antibodies, (ii) the challenges to measure those antibodies by methods that are most predictive of their influence on therapeutic efficacy of AAV gene transfer, and (iii) approaches to overcome the formidable hurdle that anti-AAV antibodies pose to the successful clinical use of AAV gene therapy.
Highlights
Thirty years ago, the Chicago Tribune published a front-page article entitled “Gene therapy poised to reinvent medicine.” While, after three humbling decades of intense research, we have not achieved this lofty goal, it is safe to say that we made tremendous progress toward establishing gene therapy as an important tool to treat both inherited as well as acquired diseases
Pre-existing anti-associated virus (AAV) antibodies are a vexing problem for AAV gene therapy because they can severely limit the patient population that could benefit from AAV gene therapy
Over the last couple of years, significant progress has been made in overcoming this formidable obstacle and to extend therapy to patients with pre-existing neutralizing antibodies, either as a result of infection by wild-type AAV or prior treatment with an AAV vector
Summary
The Chicago Tribune published a front-page article entitled “Gene therapy poised to reinvent medicine.” While, after three humbling decades of intense research, we have not achieved this lofty goal, it is safe to say that we made tremendous progress toward establishing gene therapy as an important tool to treat both inherited as well as acquired diseases. In the vast majority of past or ongoing AAV gene therapy clinical trials using AAV vectors the presence of NAbs (determined in an in vitro assay) is/was one of the exclusion criteria. I propose that, in the future, the field should report the presence of NAbs not as NAb titers but rather report the number of AAV particles that are neutralized per μl serum (or plasma) Would this facilitate the comparison of NAb assay results among different labs, it would include non-antibody inhibitory factors. Using IdeZ, a homolog of IdeS produced by a different streptococcal strain, Asokan and colleagues [30] could demonstrate that administration of IdeZ allows transduction of mice that have been passively immunized with IVIG They reported successful transduction of an NHP with pre-existing neutralizing antibodies that had been pre-injected with IdeZ [30]
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