Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema

Ting Qiu, Maria J. Chiuchiolo, Adele S. Whaley, Anthony R. Russo, Dolan Sondhi, Stephen M. Kaminsky, Ronald Crystal, Odelya E. Pagovich

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. Methods: To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Results: Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. Conclusion: A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.

Original languageEnglish
JournalAllergy: European Journal of Allergy and Clinical Immunology
DOIs
Publication statusPublished - 1 Jan 2019

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Complement C1 Inhibitor Protein
Hereditary Angioedemas
Genetic Therapy
Angioedema
Clustered Regularly Interspaced Short Palindromic Repeats
Genetic Vectors
Dependovirus
Skin
Oropharynx
Kallikreins
Serine Proteinase Inhibitors
Genitalia
Capillary Permeability
Bradykinin
Therapeutics
Heterozygote
Intravenous Administration
Androgens
Genes
Blood Vessels

Keywords

  • C1 esterase inhibitor
  • complement
  • gene therapy
  • hereditary angioedema
  • vascular permeability

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema. / Qiu, Ting; Chiuchiolo, Maria J.; Whaley, Adele S.; Russo, Anthony R.; Sondhi, Dolan; Kaminsky, Stephen M.; Crystal, Ronald; Pagovich, Odelya E.

In: Allergy: European Journal of Allergy and Clinical Immunology, 01.01.2019.

Research output: Contribution to journalArticle

Qiu, Ting ; Chiuchiolo, Maria J. ; Whaley, Adele S. ; Russo, Anthony R. ; Sondhi, Dolan ; Kaminsky, Stephen M. ; Crystal, Ronald ; Pagovich, Odelya E. / Gene therapy for C1 esterase inhibitor deficiency in a Murine Model of Hereditary angioedema. In: Allergy: European Journal of Allergy and Clinical Immunology. 2019.
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abstract = "Background: Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. Methods: To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Results: Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. Conclusion: A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.",
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AU - Qiu, Ting

AU - Chiuchiolo, Maria J.

AU - Whaley, Adele S.

AU - Russo, Anthony R.

AU - Sondhi, Dolan

AU - Kaminsky, Stephen M.

AU - Crystal, Ronald

AU - Pagovich, Odelya E.

PY - 2019/1/1

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AB - Background: Hereditary angioedema (HAE) is a life-threatening, autosomal dominant disorder characterized by unpredictable, episodic swelling of the face, upper airway, oropharynx, extremities, genitalia, and gastrointestinal tract. Almost all cases of HAE are caused by mutations in the SERPING1 gene resulting in a deficiency in functional plasma C1 esterase inhibitor (C1EI), a serine protease inhibitor that normally inhibits proteases in the contact, complement, and fibrinolytic systems. Current treatment of HAE includes long-term prophylaxis with attenuated androgens or human plasma-derived C1EI and management of acute attacks with human plasma-derived or recombinant C1EI, bradykinin, and kallikrein inhibitors, each of which requires repeated administration. As an approach to effectively treat HAE with a single treatment, we hypothesized that a one-time intravenous administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1 esterase inhibitor (AAVrh.10hC1EI) would provide sustained circulating C1EI levels sufficient to prevent angioedema episodes. Methods: To study the efficacy of AAVrh.10hC1EI, we used CRISPR/Cas9 technology to create a heterozygote C1EI-deficient mouse model (S63±) that shares characteristics associated with HAE in humans including decreased plasma C1EI and C4 levels. Phenotypically, these mice have increased vascular permeability of skin and internal organs. Results: Systemic administration of AAVrh.10hC1EI to the S63± mice resulted in sustained human C1EI activity levels above the predicted therapeutic levels and correction of the vascular leak in skin and internal organs. Conclusion: A single treatment with AAVrh.10hC1EI has the potential to provide long-term protection from angioedema attacks in affected individuals.

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KW - complement

KW - gene therapy

KW - hereditary angioedema

KW - vascular permeability

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