Successful Phenotype Improvement Following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Mar 25

PMID 27011017

Citations 16

Authors

Mary Beth Callan

Mark E Haskins

Ping Wang

Shangzhen Zhou

Katherine A High

Valder R Arruda

Affiliations

Soon will be listed here.

Abstract

Severe hemophilia A (HA) is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII) clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

Citing Articles

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life.

Doshi B, Samelson-Jones B, Nichols T, Merricks E, Siner J, French R Mol Ther Methods Clin Dev. 2024; 32(1):101205.

PMID: 38374963 PMC: 10875295. DOI: 10.1016/j.omtm.2024.101205.

Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog.

Van Gorder L, Doshi B, Willis E, Nichols T, Cook E, Everett J Mol Ther Methods Clin Dev. 2023; 31:101159.

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Viral Vectors in Gene Therapy: Where Do We Stand in 2023?.

Lundstrom K Viruses. 2023; 15(3).

PMID: 36992407 PMC: 10059137. DOI: 10.3390/v15030698.

Hemophilia A Resulting in Severe Hyperesthesia Due to Extraparenchymal Spinal Cord Hemorrhage in a Young Golden Retriever Puppy.

Lubbers C, Beukers M, Bergknut N, Paes G Vet Sci. 2022; 9(11).

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Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.

Lundgren T, Denning G, Stowell S, Spencer H, Doering C Blood Adv. 2022; 6(8):2628-2645.

PMID: 35286375 PMC: 9043920. DOI: 10.1182/bloodadvances.2021006359.

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