Gene therapy hopes for X-linked lymphoproliferative disease

Sufferers of the rare genetic disorder X-linked lymphoproliferative have a double dose of good news with the release of a new study by researchers at the Garvan Institute that might lead to a genetic therapy.

X-linked lymphoproliferative (XLP) is a rare genetic disorder that leaves sufferers particularly vulnerable to the Epstein-Barr Virus (EBV), so much so that infection can be lethal.

It is caused by mutations in SH2D1A and XIAP (BIRC4), which are associated with proper function of key immune cells, T cells and natural killer T cells as well as memory B cells.

Individuals with XLP often succumb before the age of 10, with the majority having a life expectancy of less than 40 years. However, some patients live to 50 and beyond. The question was: why?

Dr Umaimainthan Palendira and Associate Professor Stuart Tangye, from the Garvan Institute of Medical Research in Sydney found that in longer-living patients the mutated gene had reverted to its normal form.

The reversion also affected effector T cells, lending the individuals some measure of protection against EBV.

The discovery not only sheds light on the origins of XLP, but also offers hope that a gene therapy might be devised that could aid XLP sufferers.

“Somatic reversion is a fascinating clinical phenomenon, which has been characterised in a handful of other rare diseases, but never before seen in XLP,” said Associate Professor Stuart Tangye.

“Our finding highlights the importance of effector T cells in the case of XLP. This is clinically relevant because it tells us that you only need a small population of cells that are functionally capable of responding to EBV to give you good immune protection.

“If XLP patients were to receive gene therapy in future, it should be possible to confer some protection by getting the gene into a only a small number of effector T cells – a very targeted therapy.

“Gene therapy normally works by modifying bone marrow stem cells – the precursor cells which give rise to all of your blood cells, including T cells, B cells, platelets and macrophages.

“In this case, you would insert the normal gene only into naïve T cells, those T cells which have never seen infection before. When these precursor cells then encounter EBV infection, they would divide and multiply, giving rise to effector T cells, which actually work against EBV.

“While we don’t yet know exactly how somatic reversion works in XLP, we can see that it does, and that fact has clinical implications for the future.”

The research was published this week in the Journal of Experimental Medicine.