Developing Gene-Editing Tools for Heart Disease

Posted on by Janet Boyd

SUMMARY: Researchers will use novel gene-editing tools to correct damaging mutations in heart cells to help advance gene therapies for dilated cardiomyopathy, a common canine heart disease.

DESCRIPTION: Dilated cardiomyopathy (DCM) is the third most frequent type of heart disease diagnosed in dogs, with some breeds at higher risk. In Doberman pinschers, DCM prevalence is between 45% and 63%, suggesting a strong genetic component to the disease in this breed. Using stem cells from Doberman pinschers and differentiating them into heart cells, researchers will test the potential of a new gene-editing strategy to correct defects in genes important for heart function in dogs. Specifically, the team will edit a known mutation in two proteins associated with DCM and measure its impact on heart cell function. Findings will help inform future studies toward the development of gene therapies for dogs with DCM and other heart diseases.

Co-sponsored with the Morris Animal Foundation, Grant Number: D21CA-042

RESEARCHERS

Chris Martyniuk, PhD; University of Florida
Amount: $10,000

Investigation into Diet-Associated Dilated Cardiomyopathy in Dogs

Posted on by Janet Boyd

Dilated cardiomyopathy (DCM) is a serious disease of the heart muscle whereby the heart becomes enlarged with weak contractions. DCM can result in  abnormal heart rhythms, congestive heart failure or sudden death. In dogs, DCM most often occurs in large- and giant-breeds, such as Doberman  Pinschers, Boxers, Irish Wolfhounds, and Great Danes; in these dogs, survival time after diagnosis is often only months, even with aggressive medical  therapy.

Recently, veterinary cardiologists have recognized DCM more frequently in all breeds of dogs including mixed breeds, and even those not  usually associated with DCM. There is suspicion that the disease in some dogs is associated with boutique, exotic ingredient, or grain-free (BEG) diets. Some affected dogs on such diets have shown reversal or improvement of their disease after changing their diet, supporting a potential association  between consumption of a BEG diet and development of DCM. A specific cause, however, has not been identified, despite extensive nutritional testing of  the dog foods and the canine patients. Moreover, the extent of the problem is unknown because only dogs that are symptomatic for DCM have been  reported. It is possible that more dogs may be affected but not yet showing signs of heart disease.

To investigate the extent of diet-associated heart  problems in dogs, this multi-institutional team of veterinary cardiologists and nutritionists will prospectively screen a large population of apparently  healthy dogs for DCM and compare important cardiac disease measures, including ultrasound of the heart, blood biomarker and taurine concentrations,  and the frequency of DCM in dogs eating BEG versus non-BEG diets.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02661

RESEARCHERS

Darcy Adin, DVM; University of California, Davis
Amount: $5,000 (May 2019) $5,000 (November 2019)

Use of Gene Therapy to Treat Dilated Cardiomyopathy

Posted on by Janet Boyd

Dilated cardiomyopathy (DCM) is the second most common cause of heart disease in dogs,and medical management of the secondary signs is the only therapeutic option. The outcome for affected dogs depends on the stage of disease and the breed. Once diagnosed, dogs typically exhibit rapid and uniform progression to congestive heart failure (CHF), with most living less than 6 months.

Previous research has shown that heart function is critically dependent upon calcium channel function. These gate-like channels found within the wall of cardiac muscle cells open and close, allowing calcium ions to flow into the cell. Calcium influx then regulates muscle contraction. Heart disease is strongly associated with malfunctioning calcium channels within cardiac cells. Gene transfer strategies to reduce calcium cycling abnormalities improve heart function in animal models as well as in human clinical trials.

In this study, Dr. Sleeper will conduct a placebo-controlled, double blinded study to evaluate gene delivery approaches for treatment of Doberman Pinschers affected with DCM and CHF. If results show that the gene delivery slows progression of heart failure in Dobermans with DCM, the results will have significant ramifications for all dogs with heart disease, as calcium handling proteins are abnormally expressed in dogs with heart disease of varying causes.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 01760-T

RESEARCHERS

Margaret M Sleeper, VMD
University of Florida
Amount: $3,000

Juvenile Cardiomyopathy

Posted on by PWDF Admin

Our ultimate goal is to develop a mutation-based test for JDCM. There are several difficulties with JDCM, especially compared with other genetic diseases that affect your breed. Because the diagnosis of affected animals is often made after it is no longer possible to obtain blood or tissue, the most useful DNA samples cannot be obtained and therefore the strength of the pedigrees we have to work with is diminished.

Disease gene determination is often aided by finding the disease in other breeds, but this is not the case with JDCM. Despite these limitations, our goal is that we will have identified one or a battery of markers that can be used to detect the chromosomal region that contains the JDCM disease-causing allele, however, we have no way to anticipate what the “false allele” frequency will be. That has been predetermined by the breeding history of Portuguese Water Dogs and the situation may exist that we will not be able to provide a specific test until we find the mutation itself.

Co-sponsored research with the Portuguese Water Dog Club of America, Inc.

Results

A linked marker test was developed which can use either a blood sample or a cheek swab is available from the University of Pennsylvania.

Portuguese Water Dogs: JDCM – Linked Marker Test Step by Step Submission Instructions

Related News

Science Direct – A novel locus for dilated cardiomyopathy maps to canine chromosome 8

RESEARCHERS

Meg Sleeper, VMD
Paula Henthorn, PhD
University of Pennsylvania