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A - Viral Vector Development -> AAV Vectors – Preclinical and Proof-of-Concept Studies

4: Assessment of Gene Therapy Treatment in the Pompe Disease Canine Model

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Gene Therapy in Large Animal Models
Location: Room 204
Start Time: 5/16/2022 11:00
End Time: 5/16/2022 11:15

Pompe disease is a recessive lysosomal storage disease caused by a deficiency in the lysosomal enzyme acid α-glucosidase (GAA). A naturally occurring nonsense mutation in the Finnish Lapphund canines have been found to have many similarities to infantile onset Pompe disease (IOPD) in humans based on the pathophysiology in skeletal muscle, smooth muscle, motor neurons and cardiac function. The only approved treatment for Pompe disease in humans is enzyme replacement therapy (ERT) that improves striated muscle function yet does not cross the blood brain barrier and requires life-long treatment. Additionally, patients with no-endogenous activity also require immune management to prevent anti-drug antibodies. We have studied the long-term effects of systemic gene therapy using recombinant adeno-associated virus serotype 9 (rAAV9) to replace the human GAA (hGAA) gene in 6 Pompe disease affected canines. Concomitant administration of a second AAV vector to promote hGAA tolerance in target hepatocytes was given to select canines. We followed the disease progression with baseline physical exams, total health blood panel through IDEXX (including chem 27 with IDEXX SDMA®, IDEXX CBC-select®, canine Cardiopet® proBNP, total T4, canine troponin I), anti-capsid and anti-transgene antibody levels in peripheral blood, electrocardiogram (ECG), echocardiogram and photographic documentation prior to dosing. Canines were started on an immunomodulation regime of prednisone (1mg/kg) and sirolimus (1mg/m2) administered orally once a day for 7 days prior to dosing and continued post dosing for up to 3 months. On the day of dosing, prior to gene therapy delivery, a dose of diphenhydramine (1mg/kg) is given subcutaneously (SQ) followed by anti-thymocyte globulin (rabbit) (3mg/kg) intravenously (IV) and then Solu-Medrol (1mg/kg) IV. Two unaffected canines and one affected canine served as controls. One affected canine was treated at 8 months old with rAAV9-Des-hGAA at 2x1013vg/kg IV to study the impact of established disease pathology reversibility of the phenotype. One affected canine was treated at 4 weeks old with rAAV9-Des-hGAA at 3x1012vg/kg intrathecally (IT) to evaluate the option of CNS treatment only. The remaining 3 canines were treated at 3-4 weeks old with rAAV9-Des-hGAA at 3x1013 - 1x1014vg/kg and rAAV9-LSPcoGAA at 1x1012 - 1x1013 vg/kg IV simultaneously. Post dosing, we monitored anti-capsid antibody levels and vector genome circulation levels at 1 hour, 24 hours, 3, 7, and 14 days post dosing. Daily adverse event assessments and weight monitoring were performed with monthly physical exams, total health blood panel through IDEXX, anti-capsid and anti-transgene antibodies, circulating vector genomes, ECG, echocardiogram, and photographic documentation. Every 3 months gait mat analysis (ProtoKinetics®) and a hindlimb muscle biopsy is performed. Gene therapy treatment at 3-4 weeks old demonstrated significant improvement to skeletal muscle development, prevention of cardiomyopathy and prolongs the expected lifespan of Pompe affected canines. Sustained correction of GAA activity was achieved for over 9 months in all systemically treated animals. These results support the potential use of a dual vector administration to establish tolerance to GAA which is critical in IOPD. Additional studies are underway using pre-treatment with a canine specific anti-CD20 antibody to block anti-capsid antibody responses and allow subsequent dosing to maintain GAA level in the growing musculature over the life span.

Megan K. Pope1, Kirsten Coleman1, Megan Wichman1, Denise Cloutier1, Christina Cousins2, Lee Ann Mueller1, Victoria Whitehead3, Naresh Meena4, Nina Raben4, Manuela Corti1, Barry Byrne1

1Pediatrics, University of Florida, Powell Gene Therapy Center, Gainesville, FL,2Pediatrics, University of Florida, Gainesville, FL,3ProtoKinetics, Haverton, PA,4National Institutes of Health, Bethesda, MD
 M.K. Pope: None.

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