Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

  title={Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.},
  author={Pratima Chowdary and Susan Shapiro and Michael Makris and Gillian Evans and Sara Boyce and Kate L. Talks and Gerard Dolan and Ulrike M Reiss and Mark Phillips and Anne Riddell and Maria Rita Peralta and Michelle Quaye and David W. Patch and Edward G. D. Tuddenham and Allison P. Dane and Marie Watiss{\'e}e and Alison Long and Amit Nathwani},
  journal={The New England journal of medicine},
  volume={387 3},
BACKGROUND FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with… 
6 Citations

Gene Therapy in Haemophilia: Updates from Clinical Trials and Insights to Future Technologies

At the ISTH 2022 Congress, multiple oral and poster presentations were dedicated to gene therapy as a treatment for haemophilia A or B, with a number of presentations providing an insight into the ongoing research into alternative gene therapy strategies, including the use of non-viral gene transfer, gene editing strategies, and nanobodies.

Application of Gene Therapy in Hemophilia

This paper will review the bench and clinical work of gene therapy in hemophilia in recent years, and summarize the challenges and prospects of gene Therapy, so as to provide directions for future scientific research in this field.

Rational engineering of adeno‐associated virus capsid enhances human hepatocyte tropism and reduces immunogenicity

This work explored whether there was an engineering strategy that can obtain mutants with enhanced transduction efficiency coupled with reduced immunogenicity in recombinant adeno‐associated viral vectors.

Development of novel therapeutics for all individuals with CF (the future goes on).

  • M. AmaralP. Harrison
  • Biology
    Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
  • 2022



BAX 335 hemophilia B gene therapy clinical trial results - potential impact of CpG sequences on gene expression.

It is hypothesized that the loss of transgene expression could have been caused by stimulation of innate immune responses including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization.

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic

Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B.

A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids.

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice.

Assessment of the clotting times and lack of bleeding episodes support the phenotypic correction of the severe phenotype, with no clinical or laboratory evidence of risk of thrombosis, in dogs treated with AAV-8 encoding a hyperfunctional factor IX of FIX-Padua.

Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B.

In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay.

Mycophenolate mofetil impairs transduction of single-stranded adeno-associated viral vectors.

MMF impairs ssAAV-mediated liver-directed gene therapy, which is relevant for the use of this immunosuppressive agent with single-stranded vectors, and because this effect is due to impaired second-strand synthesis, theUse of MMF with scAAV seems warranted.

Preclinical Evaluation of an Engineered AAV Capsid in Non-Human Primates for the Treatment of Haemophilia B

The preclinical in vitro and in vivo evaluation of AAVS3 pseudotyped vectors and studies in a chimeric human-murine liver model revealed A AVS3 was 6-fold more efficient at transducing human hepatocytes compared with an AAV8 vector support the aim of achieving transduction of a larger proportion of hepatocytes using a lower, potentially safer dose of vector than achieved with AAV 8.

Human Immune Responses to Adeno-Associated Virus (AAV) Vectors

The current preclinical body of evidence clearly demonstrates that rAAV vectors can trigger both innate and adaptive immune responses, and data gathered from clinical trials offers key learnings on the immunogenicity of AAV vectors.

Drug interaction between tacrolimus and carbamazepine in a Japanese heart transplant recipient: a case report.

  • K. WadaM. Takada T. Nakatani
  • Medicine
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
  • 2009