Project R-11175

Targeting phosphodiesterase 4D (PDE4D) isoforms, a novel approach to boost repair in multiple sclerosis (Research)

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects young adults in the prime of their life. Even though the currently available MS therapeutics are reliable, constantly improving, and very effective in the initial stages of MS, they have limited efficacy in preventing the transition towards the progressive phase and are no longer effective in the progressive stage. During these chronic stages, when little inflammation is present, endogenous repair mechanisms (remyelination) become insufficient and cause a gradually worsening of the disability. Hence, there is an urgent need for therapies that halt disease progression and boost repair. In this project, we investigate which cognition enhancers need to be inhibited to induce repair in progressive MS. Previous work showed that blocking selected enzymes in animal models for MS enhances repair processes. However, these aspecific inhibitors are unsuitable as therapy due to severe emetic side effects (e.g. nausea). Our preliminary data show that in particular inhibition of the particular subtypes of the enzyme is promising to induce remyelination. In this project, we define exactly which subtypes are responsible for both repair and emesis. This functional segregation paves the way for the development of novel inhibitors. Due to the current lack of these inhibitors, we apply an innovative gene transfer tool to suppress the enzyme subtypes.

01 February 2021 - 31 May 2023