Cell therapy for Huntington's disease: addressing critical knowledge gaps

Cell therapies aim to replace cells that have been lost or damaged through disease, by transplanting cells into the area of loss. Such potential therapies are under consideration for a range of diseases of the brain, such as Parkinson's (PD) and Huntington's (HD) diseases. We are particularly interested in cell therapy for HD, a currently untreatable condition that is passed down through families and leads to progressive movement, thinking, and psychiatric deterioration, typically between the ages of 30-50. After transplantation into the brain, donor cells can survive and send out cellular processes to connect with particular areas of the host brain cells (their 'target' areas). We are particularly interested in cell transplantation for HD as the transplanted donor cells are placed directly into the area of cell loss and so have the opportunity to restore normal connections with the host brain. This is in contrast to conditions such as PD in which the donor cells have to be transplanted into their target regions (rather than the area of loss) and so the connections they make can never be completely normal. Thus, as well as being an area of unmet need, HD is a good 'model' in which to test whether transplanted cells can indeed restore normal connections in the brain. One of the primary changes seen in the brains of people with HD is death of a specific type of cell, called the medium spiny neuron (MSNs). Our goal is to "repair the brain" by replacing degenerated MSNs. We have shown in animal models and in early clinical trials that transplanting new MSNs into the brain results in cell grafts that survive and improve behavioural symptoms. However, the original cell source studied is very scarce and difficult to access, so it is essential to generate MSNs from new donor cell sources to allow for more widespread clinical application. We, and others, have identified stem cells as an optimal source of cells for this purpose and, over the last few years, have developed robust and promising methods to make functional MSNs from stem cells. In this project, our goal is to test these new stem cell-derived MSNs in rodents with HD. The aim is to determine whether the stem cell-derived MSNs transplants improve the same range of movement, thinking, and other behaviours that we see with transplants of the original cell source. We will use different rat models of HD to determine how robust the improvements are and which symptoms are improved, and we will compare these new stem cell-derived MSNs directly to the original 'authentic' cells that we have used in other studies. We also want to know how the cells improve these behaviours, and have a number of tools that will allow us to look at the whether the transplanted cells make direct physical contact with the host cells, whether they are electrically connected to host cells, and whether functional improvements disappear when we use special tools to temporarily switch off the grafts. We will also collect detailed molecular data that will allow us to thoroughly characterise the donor cells and grafts, and so provide the opportunity to further improve the cell therapy in the future. The information gathered in this application will be essential for us to move cell therapy for HD forward towards clinical application in a way that will be safe and continues to provide for therapeutic improvements.