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Abstract: FR-OR083

Adeno-Associated Virus-Mediated Factor H Gene Therapy in a Murine Model of Complement-Dependent Thrombotic Microangiopathy and Systemic Thrombophilia

Session Information

  • Lupus and Then Some
    November 08, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
    Abstract Time: 04:54 PM - 05:06 PM

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Ito, Daisuke, University of Pennsylvania, Philadelphia, United States
  • Kim, Hangsoo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gullipalli, Damodara, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ueda, Yoshiyasu, University of Pennsylvania, Philadelphia, United States
  • Miwa, Takashi, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Sato, Sayaka, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Zhou, Lin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Palmer, Matthew, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Xie, Jun, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  • Gao, Guangping, University of Massachusetts Medical School, Worcester, Massachusetts, United States
  • Song, Wen-Chao, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by complement dysregulation. It is characterized by thrombocytopenia, hemolytic anemia and renal injury, with up to 50% patients eventually progressing to end stage renal failure. Mutation in the C-terminal domain of factor H (FH), a critical plasma complement inhibitor, is the most common genetic cause of aHUS. Eculizumab, a humanized anti-C5 mAb, is effective for aHUS but whether lifetime treatment with Eculizumab is needed and what is the optimal length of therapy remains unknown. Here we tested the hypothesis that adeno-associated virus (AAV)-mediated FH gene therapy can correct complement dysregulation and replace anti-C5 therapy in FH mutation-related aHUS.

Methods

We used FHR/R mice which carried a homozygous mutation (W1206R) in FH. FHR/R mice developed characteristic TMA as well as macro-vessel thrombosis in multiple organs, and approximately 50% died prematurely. Twice weekly treatment of 4-week old FHR/R mice with an anti-mouse C5 mAb for 4 weeks prevented disease development as indicated by normal platelet counts and blood hemoglobin levels. The treated mice were then randomized to receive either control AAV vector or AAV-sFH encoding a mouse FH construct comprising short consensus repeats 1-4, 6-8 and 19-20 (1×1012gene copies/mouse)and anti-C5 mAb treatment was discontinued one week later.

Results

When examined at 5 weeks after AAV gene therapy (4 weeks after stopping anti-C5 mAb treatment), TMA features including thrombocytopenia, low plasma hemoglobin and elevated reticulocyte count returned to control AAV-treated but not AAV-sFH-treated mice. Six months after AAV gene therapy, 9/10 AAV-sFH-treated mice were still alive whereas only 7/20 control AAV-treated mice survived. Furthermore, severe glomerular injury and fibrin deposition in the kidney, and macro-vessel thrombosis in extra-renal organs, were detected in terminally sacrificed control AAV-treated FHR/R mice but were almost absent in AAV-sFH-treated FHR/Rmice.

Conclusion

These results demonstrate that AAV-mediated FH gene transfer can replace anti-C5 mAb treatment to provide curative therapy for TMA and other pathologies associated with FH point mutations.

Funding

  • Other NIH Support