Kidney Week

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

Daisuke Ito, MD, PhD



Daisuke Ito MD, PhD is a postdoc researcher of department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine University of Pennsylvania, Pennsylvania, USA. After graduating from Osaka University, Osaka, Japan, he trained in Internal Medicine and Nephrology at Osaka University and at Osaka Rousai Hospital, Osaka, Japan. His research interest is in complement-mediated inflammatory, autoimmune and thrombotic vasculopathy disorders. By creating gene targeted mice, his laboratory establishes mouse models of human diseases to understand disease pathogenesis and to test novel anti-complement therapies.

• Kim, Hangsoo, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Hangsoo Kim,

• Gullipalli, Damodara, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Damodara Gullipalli,

• Ueda, Yoshiyasu, University of Pennsylvania, Philadelphia, United States

Yoshiyasu Ueda,

• Miwa, Takashi, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Takashi Miwa,

• Sato, Sayaka, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Sayaka Sato,

• Zhou, Lin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Lin Zhou,

• Palmer, Matthew, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew Palmer,

• Xie, Jun, University of Massachusetts Medical School, Worcester, Massachusetts, United States

Jun Xie,

• Gao, Guangping, University of Massachusetts Medical School, Worcester, Massachusetts, United States

Guangping Gao,

• Song, Wen-Chao, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Wen-Chao Song,

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 FH^R/R mice which carried a homozygous mutation (W1206R) in FH. FH^R/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 FH^R/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 FH^R/R mice but were almost absent in AAV-sFH-treated FH^R/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 –