Investigation of the neuroinflammatory basis of the human type I interferonopathy Aicardi-Gouti?res syndrome (AGS) – Neuro-IFN

Aicardi-Goutières syndrome (AGS) is a cause of very severe brain disease in children. A lot of
evidence exists to indicate that this brain damage is due to an inflammatory process involving the
production of a chemical called interferon. Interferon is normally produced by cells in response to
infection by a virus, and some children with AGS are initially misdiagnosed as having a viral-related
disease because of the close clinical overlap of these states. In contrast to the production of interferon
secondary to virus, in AGS an excess of interferon occurs due to a primary genetic defect. Because of
the severity of the condition there is an urgent need to develop new treatments for AGS. We think this
should be possible if we better understand how the responsible genetic changes drive interferon
production.
We intend to use the very latest genetic and cell technologies to understand how brain cells are
damaged by inflammation in AGS. AGS is rare, and few parents feel able to agree to post-mortem if
their affected child dies. However, a family with affected twin girls has generously donated the brain of
one of their very recently deceased daughters. This almost unique resource will allow us to study
human neurological tissue in more detail than ever before, and using new techniques which have not
been available previously. Additionally, we are going to make use of state-of-the-art methods for
producing ‘brain cells’ in a test-tube - derived from cells of patients with AGS, so that we can study
brain tissue in the context of several different genetic sub-types of AGS. We also intend to analyse a
strain of mouse which has changes in one of the AGS-related genes as another approach to trying to
understand the human disease.
Although AGS is rare, the study of the genes and the proteins related to the disease has become of
very high scientific importance – partly because of the involvement of these genes / proteins in how
the body reponds to infection by HIV-1 (the virus that causes AIDS), and also because of an overlap
with diseases where the body attacks itself – so-called autoimmunity. Thus, not only will our work be
relevant to the children and families affected by this dreadful condition, it may also have relevance for
a much wider set of human medical disorders.