Successful Transduction with AAV Vectors after Selective Depletion of Anti-AAV Antibodies by Immunoadsorption

Orlowski, Alejandro; Katz, Michael G.; Gubara, Sarah M.; Fargnoli, Anthony S.; Fish, Kenneth; Weber, Thomas

doi:10.1016/j.omtm.2020.01.004

Cited by 55 publications

(32 citation statements)

References 25 publications

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“…More recently Bertin et al ( 26 ) and Orlowski et al ( 27 ) have demonstrated that neutralizing antibodies/factors can be removed in vitro by incubating IVIG or human sera with beads that have AAV particles covalently coupled to them. Moreover, my colleagues and I were able to demonstrate that performing hemapheresis with such beads can fully restore liver transduction in animals with NAb titers that without hemapheresis show none to negligible transduction ( 27 ). Restoration of transduction of cardiac and especially skeletal muscle was more modest, likely due to rebound of NAbs from the extracellular fluid into the bloodstream.…”

Section: Approaches To Overcome the Hurdle That Anti-aav Antibodies Pmentioning

confidence: 99%

“…Restoration of transduction of cardiac and especially skeletal muscle was more modest, likely due to rebound of NAbs from the extracellular fluid into the bloodstream. Unfortunately, technical limitations prevented us from performing multiple rounds of hemapheresis over several days ( 27 ). Multiple rounds of hemapheresis over the span of several days can easily be performed in humans ( 25 ), so it is highly likely that the rebound limitation in rats could be easily overcome in humans.…”

Section: Approaches To Overcome the Hurdle That Anti-aav Antibodies Pmentioning

confidence: 99%

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Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions

Weber

2021

Front. Immunol.

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101

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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.

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Section: Approaches To Overcome the Hurdle That Anti-aav Antibodies Pmentioning

confidence: 99%

Section: Approaches To Overcome the Hurdle That Anti-aav Antibodies Pmentioning

confidence: 99%

Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions

Weber

2021

Front. Immunol.

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101

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“…Besides capsid engineering, alternative approaches have also been explored to overcome the NAb issue. For instance, recent reports showed that plasmapheresis could efficiently remove NAbs to permit AAV re-delivery and transgene expression in rodent models, which can serve as an alternative solution when anti-AAV NAbs cannot be bypassed through other means [ 72 , 73 ]. Nonetheless, host immune responses to intravenous AAV delivery is far more complex than previously known [ 67 ].…”

Section: Overcoming the Current Hurdles In Aav-based Therapymentioning

confidence: 99%

Evolving AAV-delivered therapeutics towards ultimate cures

Urip

Zhang

et al. 2021

J Mol Med

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Gene therapy has entered a new era after decades-long efforts, where the recombinant adeno-associated virus (AAV) has stood out as the most potent vector for in vivo gene transfer and demonstrated excellent efficacy and safety profiles in numerous preclinical and clinical studies. Since the first AAV-derived therapeutics Glybera was approved by the European Medicines Agency (EMA) in 2012, there is an increasing number of AAV-based gene augmentation therapies that have been developed and tested for treating incurable genetic diseases. In the subsequent years, the United States Food and Drug Administration (FDA) approved two additional AAV gene therapy products, Luxturna and Zolgensma, to be launched into the market. Recent breakthroughs in genome editing tools and the combined use with AAV vectors have introduced new therapeutic modalities using somatic gene editing strategies. The promising outcomes from preclinical studies have prompted the continuous evolution of AAV-delivered therapeutics and broadened the scope of treatment options for untreatable diseases. Here, we describe the clinical updates of AAV gene therapies and the latest development using AAV to deliver the CRISPR components as gene editing therapeutics. We also discuss the major challenges and safety concerns associated with AAV delivery and CRISPR therapeutics, and highlight the recent achievement and toxicity issues reported from clinical applications.

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“…To date, no solutions have been found to this conundrum, although it should be noted one group delivering AAV5‐FIX reports successful transgene transfer in the presence of anti‐AAV5 antibodies, 115 while a second group finds the opposite result 116 . Immunosuppression to prevent anti‐AAV antibody formation postinfusion has been suggested, as has plasmapheresis or immunoadsorption to eliminate pre‐existing anti‐AAV antibody, but to date, no clinical studies have implemented any of these modalities 117,118 . Specific AAV antibody immunoadsorption is particularly attractive since plasmapheresis depletes all IgG.…”

Section: The Dream Of a Cure Realized… For Somementioning

confidence: 99%

Uncertainty in an era of transformative therapy for haemophilia: Addressing the unknowns

Pierce

2020

Haemophilia

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Haemophilia is at the dawn of a new era in therapeutic management, one that can generate greater protection from bleeding and a functional cure in some individuals. Prior advances in protein engineering and monoclonal antibody technology have facilitated therapeutic options to maintain decreased risk of bleeding and less burdensome treatment. The use of gene transfer, first proposed in 1971 for monogenic diseases, is emerging as an effective long‐term treatment for a variety of diseases. Transfer of functional factor VIII (FVIII) and factor IX (FIX) genes has witnessed a series of advances and setbacks since the first non‐clinical experiments in animals were initiated nearly 30 years ago. More recently, multiyear therapeutic levels of FVIII and FIX activity have been achieved in human clinical trials, translated into meaningful clinical benefit and a functional cure. While clinical progress has been definitive, many questions remain unanswered as prelicensure phase 3 clinical trials are underway. These unanswered questions translate into a state of uncertainty about the known unknowns and unknown unknowns intrinsic to any new therapeutic platform. Accepting this modality as a means to functionally cure haemophilia also means accepting the uncertainty regarding the biology of viral vector‐mediated gene transfer, which remains inadequately understood. Gene therapy is a far more complex biological ‘drug’ than small molecule and protein drugs, where manufacturing processes and the drugs themselves are now well characterized. Extent of community acceptance of uncertainty and acknowledgement of the need for an uncompromising drive for answers to the unknowns will characterize the introduction of this first generation of gene therapy for haemophilia to the wider patient population in both resource‐rich and resource‐poor countries.

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Successful Transduction with AAV Vectors after Selective Depletion of Anti-AAV Antibodies by Immunoadsorption

Cited by 55 publications

References 25 publications

Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions

Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions

Evolving AAV-delivered therapeutics towards ultimate cures

Uncertainty in an era of transformative therapy for haemophilia: Addressing the unknowns

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