A23 What can HD learn from the development of dimethyl fumarate (Tecfidera®) for multiple sclerosis?

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system in which the myelin sheaths that protect axons of neurons and are critical for rapid signal transduction become damaged due to attack by autoreactive immune components such as T and B cells, myeloid cells, autoantibodies and complement. Demyelination leads to impaired neuronal signal transduction, increased oxidative stress, and increased potential for axonal damage and neuronal degeneration. MS most frequently presents in relapsing-remitting forms (RRMS) with isolated attacks followed by periods of recovery and remyelination. Approximately 50% of RRMS cases convert over time to a secondary progressive form of MS in which neurological disability does not recover, and approximately 10% of MS patients can display a primary progressive form of MS with minimal clinical relapses and steady accumulation of disability and neuronal loss. Disease-modifying treatments for MS have been developed primarily to control the immune-mediated attacks of RRMS, in part because these aspects of MS are adequately modelled by current rodent models such as EAE. Approved MS treatments include agents to block cell trafficking into the CNS, cell ablation by antibodies or anti-proliferative drugs, and therapeutics which modify T cell responses. A potentially different mechanism is attributed to delayed-release dimethyl fumarate (DMF), also known as gastric-resistant DMF, which is marketed under the brand name Tecfidera ® for treating relapsing MS in the US, and in the EU, Australia, and other countries. During development, DMF has been hypothesised to work through multiple potential mechanisms including increased energetics, anti-inflammatory activities, and more recently, as stimulating transcription of endogenous antioxidant and cytoprotective genes through activation of the transcription factor Nrf2. In this talk, I will provide an overview of the development of DMF and our current understanding of its therapeutic actions, and discuss potential challenges and pitfalls of developing neuroprotective agents for neurodegenerative diseases including Huntington’s disease.