Potential for cellular stress response to hepatic factor VIII expression from AAV vector

Zolotukhin, Irene; Markusic, David M.; Palaschak, Brett; Hoffman, Brad E.; Srikanthan, Meera; Herzog, Roland W.

doi:10.1038/mtm.2016.63

Cited by 54 publications

(52 citation statements)

References 51 publications

(68 reference statements)

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“…On the other hand, despite the initial high-level FVIII expression in hepatocyte-targeted FVIII gene therapy, a strong immune response is observed and inhibitors are developed following naked DNA transfer in HA mice (80). Moreover, it has been demonstrated that high levels of FVIII expression in hepatocytes are associated with transient endoplasmic reticulum stress and the consequent activation of unfolded protein response, with a correlation between FVIII expression and inhibitor formation (81,82).…”

Section: Gene Therapymentioning

confidence: 99%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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Replacement therapy with coagulation factor VIII (FVIII) represents the current clinical treatment for patients affected by hemophilia A (HA). This treatment while effective is, however, hampered by the formation of antibodies which inhibit the activity of infused FVIII in up to 30% of treated patients. Immune tolerance induction (ITI) protocols, which envisage frequent infusions of high doses of FVIII to confront this side effect, dramatically increase the already high costs associated to a patient's therapy and are not always effective in all treated patients. Therefore, there are clear unmet needs that must be addressed in order to improve the outcome of these treatments for HA patients. Taking advantage of preclinical mouse models of hemophilia, several strategies have been proposed in recent years to prevent inhibitor formation and eradicate the pre-existing immunity to FVIII inhibitor positive patients. Herein, we will review some of the most promising strategies developed to avoid and eradicate inhibitors, including the use of immunomodulatory drugs or molecules, oral or transplacental delivery as well as cell and gene therapy approaches. The goal is to improve and potentiate the current ITI protocols and eventually make them obsolete.

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Section: Gene Therapymentioning

confidence: 99%

Escape or Fight: Inhibitors in Hemophilia A

Merlin

Follenzi

2020

Front. Immunol.

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“…This may reflect differences in generation of long-lived plasma cells between the two species in response to FVIII, which may be harder to suppress. However, preventive tolerance induction has been accomplished in the mice using optimized expression cassettes [84, 95, 96]. High levels of FVIII expression in hepatocytes has some potential for induction of a cellular stress response, which however does not appear to increase immunogenicity [96, 97].…”

Section: Immune Tolerance Induction To the Transgene Product By LImentioning

confidence: 99%

“…However, preventive tolerance induction has been accomplished in the mice using optimized expression cassettes [84, 95, 96]. High levels of FVIII expression in hepatocytes has some potential for induction of a cellular stress response, which however does not appear to increase immunogenicity [96, 97]. An alternative method to reverse FVIII inhibitors is the combination of B cell depletion with monoclonal anti-CD20 and rapamycin, which work synergistically on the B and T cell compartments [98].…”

Section: Immune Tolerance Induction To the Transgene Product By LImentioning

confidence: 99%

Complexity of immune responses to AAV transgene products – Example of factor IX

Herzog

2019

Cellular Immunology

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After two decades of research, in vivo gene transfer with adeno-associated viral (AAV) vectors has now resulted in successful treatments and even cures for several human diseases. However, the potential for immune responses against the therapeutic gene products remains one of the concerns as this approach is broadened to more patients, diverse diseases, and target organs. Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models. Findings from these studies have not only influenced clinical trial design but have broader implications for other diseases. The impact of vector design and dose, as well as target organ/route of administration on humoral and cellular immune responses are reviewed. Furthermore, the potential for tolerance induction by hepatic gene transfer or combination with immune modulation is discussed.

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“…Zolotukhin and colleagues used a codon‐optimized BDD‐FVIII within an AAV vector to transduce wild‐type C57BL/6 mice . Although there was no resultant increase in ALT levels, there was upregulation of UPR sentinel chaperone proteins at increased doses of the AAV vector.…”

Section: Challenges To Be Addressed With Bioengineered Fviii Constructsmentioning

confidence: 99%

Bioengineered molecules for the management of haemophilia: Promise and remaining challenges

Pipe

2018

Haemophilia

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Recombinant DNA technology has led to accelerating introduction of novel therapeutics for the treatment of haemophilia. This technology has driven the development of recombinant clotting factors, extended half-life clotting factors, alternative biologics to promote haemostasis and enabled the launch of the gene therapy era for haemophilia. At the core of this technology is the ability to study the structure and function of the native molecules and to apply rational bioengineering to overcome limitations to the existing therapies. Through the study of haemophilia-causing mutations, site-directed mutagenesis, detailed structural models and a wide repertoire of animal models, new bioengineering strategies are helping overcome some of the remaining limitations and challenges of traditional clotting factor concentrates. Some of these bioengineering strategies are now being partnered with improvements in vectorology leading to the first wave of successful gene therapy approaches. This study will review past and present bioengineered molecules that are advancing care for haemophilia as well as novel approaches that promise to continue to improve care and outcomes for patients with haemophilia.

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Potential for cellular stress response to hepatic factor VIII expression from AAV vector

Cited by 54 publications

References 51 publications

Escape or Fight: Inhibitors in Hemophilia A

Escape or Fight: Inhibitors in Hemophilia A

Complexity of immune responses to AAV transgene products – Example of factor IX

Bioengineered molecules for the management of haemophilia: Promise and remaining challenges

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