Dr David Connolly, Professor Brian Catchpole, Dr Jay Dudhia (RVC) and Hannah Hodgkiss-Geere (Liverpool Vet School) has been awarded a grant by Petplan Charitable Trust for a project called: "Avoid rejection to fix a broken heart: assessing the feasibility of allogeneic stem cell therapy for canine dilated cardiomyopathy"
Dilated cardiomyopathy (DCM) is the second most common heart disease of dogs and is considered to have an underlying genetic basis in the majority of cases. For reasons that are not well understood the putative genetic abnormality affects the ability of the heart muscle to contract robustly and efficiently and over time this results in the muscle stretching causing the heart to dramatically increase in size (dilate). The poorly contracting dilated heart eventually deteriorates leading to sign of heart failure.
Current treatment for DCM is directed towards controlling the clinical signs of heart failure such as breathlessness, weakness and serious rhythm disturbance which can cause sudden death. However none of the medications actually help repair the damaged heart muscle or reduce disease progression. Early results from clinical trials in human patients with DCM have shown improved heart pumping function and outcomes with the use of stem cell therapy. The stem cells were either obtained from the patient’s fat or bone marrow or alternatively from small pieces of the patients own heart. Fat or bone marrow derived stem cells obtained from non-related donors have also been successfully used. Unfortunately similar improvements in heart function were not seen when bone marrow derived stem cells were used to treat Doberman dogs with DCM suggesting that this cell type may not be ideal.
Adult stem cells are found in most tissues in the body and they have special characteristics that differentiate them from other adult cells. Normal adult cells have fully matured into their final cell type e.g. muscle cell or nerve cell and they cannot divide and multiply anymore. Stem cells have more immature characteristics; they still have the ability to divide and the new “daughter” cells can often mature into a limited number of different cell types depending on their surrounding environment. For instance if these cells are place into the heart they can make new blood vessels and muscle whereas in the brain they may form nerve tissue.
Based on studies in experimental pigs and human patients we believe that treating dogs with DCM using stem cells derived from the heart itself will give the best result and help repair the damaged heart muscle. However obtaining heart tissue from live dogs especially those with severe DCM is not possible so an alternative is to use cardiac tissue from healthy young dogs that have had to be euthanized for reasons such as trauma. This would only be done following written owner consent and university ethical approval.
Although we know from numerous studies in animals and humans that it is possible to inject fat or bone marrow derived stem cells from one individual into an unrelated individual (allogeneic transfer) without causing a severe immune reaction this has never been examined for stem cells derived from cardiac tissue. It is this question that forms the basis of our research and grant proposal. We aim to explore the immunological characteristics and immune reactivity of cardiac derived stem cells and compare them with fat derived stem cells from dogs using well established laboratory techniques.
Specifically our aims are:
- To grow canine cardiac (CSCs) and fat derived (MSCs) stem cells in the laboratory and perform quality control tests to ensure that our stem cell populations are precise and pure.
- To assess the immunological profile of MSCs and CSCs using antibodies to determine which immunological markers are present on the cell surface.
- To assess how immunologically reactive the stem cells are when MSCs and CSCs from different dog are mixed together. We can measure this using an assay in the laboratory.
If we can prove in the laboratory that CSCs from unrelated dogs do not cause a dangerous immune reaction when mixed together; this will open up their therapeutic potential for the treatment of DCM in dogs.
This approach will have advantages over trying to use CSCs from dogs already affected with DCM:
- Previous research shows that CSCs from cardiac tissue obtained from younger dogs with a healthy heart will grow and function more efficiently than older cells from sick dogs
- We will be able to grow a large quantity of stem cells from a single donor heart which can be frozen down and stored ready for when needed. This means that we can treat a large number of dogs with DCM using a single donor heart.
- As DCM most likely has a genetic basis then by using stem cells from a dog with a healthy heart we can ensure that the stem cells do not carry the genetic abnormality that may cause the heart disease.
This project will act as a proof of principle for the use of cardiac derived stem cells in the treatment of dogs with DCM for which there is at present no other efficacious treatment.