Metabolic gene therapy in a canine with pulmonary hypertension secondary to degenerative mitral valve disease

Abstract

Myxomatous mitral valve disease (MMVD) stands out as the most prevalent acquired canine heart disease. Its occurrence can reach up to 40% in small breed dogs and escalates in geriatric canine populations. MMVD leads to thickening and incomplete coaptation of valve leaflets during systole, resulting in secondary mitral valve regurgitation. Serious complications may arise concurrently with the worsening of mitral valve regurgitation, including left-and right-sided congestive heart failure, and pulmonary hypertension (PH). Ultimately, the PH progression might contribute to the patient's demise or to the owner's decision of euthanasia. Most currently available FDA-approved therapies for PH are costly and aim to address the imbalance between vasoconstriction and vasodilation to restore endothelial cell function. However, none of these medications impact the molecular dysfunction of cells or impede the advancement of pulmonary vascular and right ventricular remodeling. Recent evidence has showcased successful gene therapy approaches in laboratory animal models of PH. In this manuscript, we summarize the latest advancements in gene therapy for the treatment of PH in animals. The manuscript incorporates original data showcasing sample presentations, along with non-invasive hemodynamic assessments. Our findings demonstrate that the use of metabolic gene therapy, combining synthetic adeno-associated virus with acid ceramidase, has the potential to significantly reduce the need for drug treatment and improve spontaneously occurring PH in dogs.

Keywords: canine cardiovascular disease; degenerative mitral valve disease; gene therapy; pulmonary hypertension; sphingolipids metabolism.

Figure 1

Gene construct explored for pulmonary hypertension. AM: Adrenomedullin; HGF: Hepatocyte Growth Factor; HIF-1α/shRNA: Hypoxia-Inducible Factor 1-alpha/short hairpin RNA; sCD40L: Soluble CD40 Ligand; Twist1-PDGFB: Twist1-Platelet-Derived Growth Factor Subunit B; VEGF: Vascular Endothelial Growth Factor; NO: Nitric Oxide; CGRP: Calcitonin Gene-Related Peptide; Kv1.5: Voltage-Gated Potassium Channel Subunit Kv1.5; BMPR-II: Bone Morphogenetic Protein Receptor Type II; Tph1: Tryptophan Hydroxylase1; FoxO1: Forkhead Box Protein O1; ANP: Atrial Natriuretic Peptide; TIMP-1: Tissue Inhibitor of Metalloproteinases 1; sTIE2: Soluble TIE2; IL-10: Interleukin-10; PGIS: Prostacyclin Synthase; SERCA2a: Sarco/Endoplasmic Reticulum Calcium ATPase 2a; AC: Acid Ceramidase.

Figure 2

(A,C) Baseline Doppler echocardiographic imaging (using an S5 phased array transducer, Vivid E95, General Electric) of tricuspid valve insufficiency from the left parasternal, apical four-chamber view. Color Doppler flow (C) and continuous wave spectral Doppler measurement of the systolic pressure gradient (108.2 mmHg, approximately 4.3 times the expected normal) across the valve (A). (D,B) Doppler echocardiographic imaging (using an S5 phased array transducer, Vivid E95, General Electric) of tricuspid valve insufficiency from the left parasternal, apical four-chamber view, 146 days following baseline imaging. Color Doppler flow (C) and continuous wave spectral Doppler measurement of the systolic pressure gradient (62.5 mmHg, approximately 2.5 times the expected normal) across the valve (A). (E) Before gene therapy Caudal (“Posterior”) Vena Cava Diameter. (F) After gene therapy Caudal (“Posterior”) Vena Cava Diameter.