Development of a lentiviral gene therapy vector for treatment of haemophagocytic lymphohistiocytosis (HLH) due to perforin deficiency

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HLH is a devastating disorder in which the immune system is unable to control infection and then becomes highly abnormal causing fever, enlargement of the liver and spleen and destruction of blood cells. The condition is caused by defects in certain genes and often affects children early in life. The only treatment is a bone marrow transplant which can be successful if a matched donor is available but is associated with significant complications if HLH is not controlled or if no good donor is available for transplant. To offer a safer and equally effective alternative, we want to use gene therapy to correct the condition. In early studies we have shown that if we introduce the perforin gene into bone marrow stem cells of perforin deficient mice and transplant them in perforin deficient recipients, we can restore the ability of the immune system to control infection and prevent HLH. These are very promising early data but to take this through to being a treatment for patients, we have perform a series of studies to show that it is both effective and safe.We therefore plan to conduct a number of studies in different models of perforin deficiency with an optimal gene therapy vector that carries the perforin gene. We will correct bone marrow stem cells as previously but we will also challenge the corrected mice with a live infection to see if this prevents the onset of HLH. We will also also look at another approach and correct just blood (not bone marrow) immune cells as this may be a safer way of controlling disease.Before taking this to patients, we also need to show that this treatment is safe. We will do this in a number of ways. We will show that once cells have been corrected, there is no evidence that they can then become cancerous because of the way the gene has ben inserted into the cells. We will also ensure that by introducing the gene into stem cells, this does not alter the function of the stem cell pool.If we can show both effectiveness and safety in these studies, then this strategy can be taken forward for a clinical trial in HLH patients.