Treating ALS by Targeting Pathological TDP-43
Abstract
In amyotrophic lateral sclerosis (ALS), the nerve cells controlling movement become dysfunctional and then die. The muscle fibers controlled by the diseased nerve cells waste away without signals from the nerves. In over 90% of ALS cases, the diseased nerve cells accumulate abnormal, modified, and inappropriately located TDP-43 protein. It is thought this abnormal TDP-43 protein is a major driver in the disease process because in rare families with inherited ALS, mutations in the gene coding for TDP-43 cause ALS and abnormal TDP-43. Similarly, in non-inherited ALS, TDP-43 in nerve cells nearly always becomes abnormal in the absence of mutations. Thus, TDP-43 is a major disease protein in ALS. In animals used to model diseases, such as mice, one can genetically introduce a regulatable TDP-43 gene (transgene) that can be turned on or off. In this mouse model, when the TDP-43 transgene is turned on, abnormal TDP-43 accumulates, nerve cells become diseased, muscles become weak, paralysis ensues, and death then follows, much like authentic ALS in humans. However, if the transgene is turned off before end stage of the disease process, abnormal TDP-43 dissipates and animals can recover near normal muscle function. Taken together, these observations suggest that abnormal TDP-43 is a major contributor to the disease process in ALS; furthermore, preventing the accumulation of abnormal TDP-43 would likely be of therapeutic benefit. However, to date, no therapies targeting TDP-43 have been tried in the clinic. Our previous research showed that enzymes called kinases can control the accumulation of abnormal TDP-43. A specific pair of kinase enzymes called TTBK1 and TTBK2 can promote the accumulation of abnormal TDP-43. Furthermore, TTBK1 and TTBK2 become hyperactive in ALS. Taken together, these findings suggest drugs inhibiting TTBK1/2 activity could prevent the accumulation of abnormal TDP-43. To test this hypothesis, we propose to screen for new drugs that block TTBK1/2 activity and then test whether or not TTBK1/2 inhibitor drugs prevent accumulation of abnormal TDP-43 and the resulting muscle weakness. Previous drug development efforts blocking kinases have been successful for other diseases. Our goal is to find drugs that block TTBK1/2 activity on TDP-43, thus preventing its accumulation in cultured human cells. We will then test effective inhibitors in the regulatable TDP-43 mouse model of ALS. Drugs found to be effective in mice will be developed and optimized further. The ultimate goal of our work is finding compounds suitable for therapeutic intervention trials in ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610550
Entities
People
- Brian Kraemer
Organizations
- Seattle Institute for Biomedical and Clinical Research
- United States Army