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Author Notes:

Correspondence: H. Trent Spencer, hspence@emory.edu or Christopher B. Doering, cdoerin@emory.edu

Author contributions: SP, TL, HS, and CD drafted and edited the manuscript.

Disclosures: CD and HS are co-founders of Expression Therapeutics and own equity in the company. Expression Therapeutics owns the intellectual property associated with ET3.

The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Research Funding:

This work was supported by funding from Hemophilia of Georgia and the National Institutes of Health/National Heart, Lung and Blood Institute (award numbers R44HL117511, R44HL110448, U54HL112309, U54HL141981, and R01 HL137128 to CD, HS).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • gene therapy
  • hemophilia A
  • inhibitors
  • lentiviral (LV) vector
  • adeno-associated viral vectors
  • hematopoietic (stem) cells
  • factor VIII (fVIII)
  • Regulatory t cells
  • Human factor VIII
  • Coagulation factor-VIII
  • Hemophilia A mice
  • Sinusoidal endothelial cells
  • High level expression
  • Porcine factor VIII
  • Sustained phenotypic correction
  • Antigen specific tolerance
  • Hematopoietic stem cells

The Immune Response to the fVIII Gene Therapy in Preclinical Models


Journal Title:

Frontiers in Immunology


Volume 11


, Pages 494-494

Type of Work:

Article | Final Publisher PDF


Neutralizing antibodies to factor VIII (fVIII), referred to as “inhibitors,” remain the most challenging complication post-fVIII replacement therapy. Preclinical development of novel fVIII products involves studies incorporating hemophilia A (HA) and wild-type animal models. Though immunogenicity is a critical aspect of preclinical pharmacology studies, gene therapy studies tend to focus on fVIII expression levels without major consideration for immunogenicity. Therefore, little clarity exists on whether preclinical testing can be predictive of clinical immunogenicity risk. Despite this, but perhaps due to the potential for transformative benefits, clinical gene therapy trials have progressed rapidly. In more than two decades, no inhibitors have been observed. However, all trials are conducted in previously treated patients without a history of inhibitors. The current review thus focuses on our understanding of preclinical immunogenicity for HA gene therapy candidates and the potential indication for inhibitor treatment, with a focus on product- and platform-specific determinants, including fVIII transgene sequence composition and tissue/vector biodistribution. Currently, the two leading clinical gene therapy vectors are adeno-associated viral (AAV) and lentiviral (LV) vectors. For HA applications, AAV vectors are liver-tropic and employ synthetic, high-expressing, liver-specific promoters. Factors including vector serotype and biodistribution, transcriptional regulatory elements, transgene sequence, dosing, liver immunoprivilege, and host immune status may contribute to tipping the scale between immunogenicity and tolerance. Many of these factors can also be important in delivery of LV-fVIII gene therapy, especially when delivered intravenously for liver-directed fVIII expression. However, ex vivo LV-fVIII targeting and transplantation of hematopoietic stem and progenitor cells (HSPC) has been demonstrated to achieve durable and curative fVIII production without inhibitor development in preclinical models. A critical variable appears to be pre-transplantation conditioning regimens that suppress and/or ablate T cells. Additionally, we and others have demonstrated the potential of LV-fVIII HSPC and liver-directed AAV-fVIII gene therapy to eradicate pre-existing inhibitors in murine and canine models of HA, respectively. Future preclinical studies will be essential to elucidate immune mechanism(s) at play in the context of gene therapy for HA, as well as strategies for preventing adverse immune responses and promoting immune tolerance even in the setting of pre-existing inhibitors.

Copyright information:

© 2020 Patel, Lundgren, Spencer and Doering.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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