Valder
 
R.
 
Arruda
MD, PhD
Email: 
arruda@email.chop.edu
Address: 
The Children's Hospital of Philadelphia 5056 Colket Translational Research Building 3501 Civic Center Boulevard
215-590-4907
Affiliations
Expertise

CVI Program Unit(s):
Thrombosis / Hemostasis


CVI Research Description:
Our laboratory is interested in the development of gene-based strategies for the treatment of bleeding and thrombotic diseases. In a collaborative effort, we and others have carried out early-phase clinical studies on adeno-associated viral (AAV) vectors for the treatment of severe hemophilia B (factor IX deficiency). Current projects are focused on translational research studies on the efficacy and safety of intravascular delivery of AAV vectors to skeletal muscle or liver of dogs and mice with severe hemophilia. We are also identifying biological factors that modulate AAV vectors transduction and the risk of inadvertent germline transmission in animal models.

Blockage of blood vessels causes many serious human diseases, including myocardial infarct, ischemic strokes, and venous thrombosis. They contribute to the mortality and morbidity of septic shock, chronic inflammatory injury, and vascular complications of systemic diseases. The protein C anticoagulant pathway plays a major role in the interface between coagulation and inflammatory processes. Venous thrombosis is most commonly the result of defects in the proteins that participate in the protein C anticoagulant pathway. Activated Protein C (APC) mediates anticoagulant effects and signals cellular responses that are anti-inflammatory in nature. The current notion that occlusive vascular diseases such as atherosclerosis are forms of systemic diseases in which underlying inflammatory and thrombotic processes play a critical role led us to postulate that APC could offer an alternative therapeutic option. Ongoing studies are aimed at elucidating in vivo functions of APC in a series of animal models for thrombotic and/or inflammatory diseases.

Together, these studies should improve our understanding of the interface of blood coagulation and inflammation and to identify novel therapeutic strategies for coagulation disorders and other diseases.

Research Interests

Gene therapy for the treatment of disorders of hemostasis and thrombosis.

Key words: AAV-Hemophilia-Thrombosis-Coagulation-Germline.

Description of Research

Our laboratory is interested in the development of gene-based strategies for the treatment of bleeding and thrombotic diseases. In a collaborative effort, we and others have carried out early-phase clinical studies on adeno-associated viral (AAV) vectors for the treatment of severe hemophilia B (factor IX deficiency). Current projects are focused on translational research studies on the efficacy and safety of intravascular delivery of AAV vectors to skeletal muscle or liver of dogs and mice with severe hemophilia. We are also identifying biological factors that modulate AAV vectors transduction and the risk of inadvertent germline transmission in animal models.

Blockage of blood vessels causes many serious human diseases, including myocardial infarct, ischemic strokes, and venous thrombosis. They contribute to the mortality and morbidity of septic shock, chronic inflammatory injury, and vascular complications of systemic diseases. The protein C anticoagulant pathway plays a major role in the interface between coagulation and inflammatory processes. Venous thrombosis is most commonly the result of defects in the proteins that participate in the protein C anticoagulant pathway. Activated Protein C (APC) mediates anticoagulant effects and signals cellular responses that are anti-inflammatory in nature. The current notion that occlusive vascular diseases such as atherosclerosis are forms of systemic diseases in which underlying inflammatory and thrombotic processes play a critical role led us to postulate that APC could offer an alternative therapeutic option. Ongoing studies are aimed at elucidating in vivo functions of APC in a series of animal models for thrombotic and/or inflammatory diseases.

Together, these studies should improve our understanding of the interface of blood coagulation and inflammation and to identify novel therapeutic strategies for coagulation disorders and other diseases.


Rotation projects

- Interface between coagulation and efficacy in gene transfer by viral vectors.
-Characterization of animal model for hypercoagulability.
-Development of AAV vectors encoding clotting factors and natural anticoagulants.

Lab personnel:
Julie Crudele, Graduate Student;
Joshua Siner, Research Technician

Appointments
Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2000 – 2007)
Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2007– present)
Education
Ph.D., Molecular Biology, University of Campianas, Sao Paolo, Brazil (1995)
M.D., Medicine / Hematology, Faculty of Medicine of Triangulo Mineiro, MB, Brazil (1987)
Selected Publications
Mingozzi F, Liu Y-L, Dobrzynzki E, Kaufhold A, Liu JH, Wang YQ, Arruda VR, High KA, Herzog RW. Induction of immune tolerance to coagulation factor IX antigen in in vivo hepatic gene transfer. Journal of Clinical Investigation. Vol 111. 2003:1347-1356.
Manno CS, Chew A, Hutchison S, Larson PJ, Herzog RW, Arruda VR, Tai SJ, Ragni MV, Thompson A, Ozelo M, Couto LB, Leonard DGB, Johnson FA, McClelland A, Scallan C, Skarsgaard E, Flake AW, Kay MA, High KA, Glader B. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. Vol 101. 2003:2963-2972.
High KA, Herzog R, Arruda V. AAV-mediated gene transfer to liver. Blood. Vol 101. 2003:3338-3339.
Mount MJ, Herzog R, Arruda VR, Tillson M, Lothrop CD, High KA. Sustained high-level correction of inhibitor-prone hemophilia B dogs by liver-directed gene therapy. Blood. Vol 99. 2002:2670-2676.
Herzog RW, Fields PA, Arruda VR, Brewbaker J, Armstrong EA, McClintock D, Bellinger D, Couto LB, Nichols TC, High KA. Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy for hemophilia B. Human Gene Therapy. Vol 13. 2002:1281-1291.
Mingozzi F, Schuettrumpf J, Arruda VR, Lui Y, Liu Y-L, High KA, Xiao W, Herzog RW. Improved hepatic gene transfer by using an adeno-associated virus serotype 5 vector. J Virol. Vol 76. 2002:10497-10502.
Herzog RW, Mingozzi F, Arruda VR, Liu Y-L, High KA. Improved efficacy of hepatic gene transfer by use of an AAV serotype-5 vector. Molecular Therapy. Vol 5. 2002:S39.
Schuettrumpf J, Liu Y-L, Herzog RW, High KA, Arruda VR. Effects of anticoagulant drugs on in vivo AAV-mediated live-directed gene transfer. Molecular Therapy. Vol 5. 2002:S40.
Couto L, Jian H, Scallan Ci, Qian X, Patarroyo-White S, Parker A, Liu T, Chen H, Powell S, Wright F, Tinlin S, Webster S, Lillicrap D, Sarkar R, Kazazian H, Arruda V, High K, Meuse L, Ohashi K, Kay M, McClelland A. Hemophilia A gene therapy in mouse and dog models using an AAV-FVIII vector. Molecular Therapy. Vol 5. 2002:S84.
Scallan C, Liu T, Parker A, Patarroyo-White S, Chen H, McClelland A, Powell S, Wright F, Sarkar R, Kazazian H, Arruda V, High K, Meuse L, Ohashi K, Kay M, Couto L. Phenotypic correction of hemophilia A using a dual AAV vector approach. Molecular Therapy. Vol 5. 2002:S86.