The Use of NF kappa B Inhibitors in Treating Rett Syndrome

Sponsored by the International Rett Syndrome Foundation HeArt Grant.

The overall objective of this research project is to determine the potential benefit of treating children with RTT with drugs that inhibit the NF k B pathway and are currently being developed to treat cancer and inflammatory disease. The drugs are potentially beneficial because of our studies showing over active NF kappa B signaling in cells expressing dysfunctional MeCP2. Moreover, a literature review reveals an overlap between mechanisms regulated by MeCP2 and NF k B. For example, macrophage mediated glutamate release is enhanced in Mecp2 deficient macrophages and blocked by NF k B inhibitors.

Many inhibitors have been described that target different steps in the NF k B pathway. Inhibitors most appropriate for treating RTT would be those working at the same step that is affected by MeCP2. Other inhibitors would likely have non-specific effects. To distinguish the inhibitors with the greatest potential therapeutic value, we will examine the multi-step NF k B pathway in MECP2 deficient and MECP2 over expressing, THP1 monocyte cell line treated with TLR ligands. NF k B inhibitors that target the step affected by MeCP2 will be examined for their effectiveness in restoring NF k B activity to levels observed in cells expressing MECP2.

To verify the inhibitors restore mechanisms regulated by Mecp2 and NF kappa B, we will examine glutamate release from macrophages from Mecp2 null macrophages and blood monocytes from children with RTT. Human blood monocytes enable us to predict whether the drug will work in vivo in children. In future studies, the effectiveness of these NF k B inhibitors will be examined in Mecp2 null mice for increasing survival, preventing weight loss and restoring motor function.