Evaluating the therapeutic potential of hypoxia mimetics in inflammatory demyelinating disease

Multiple sclerosis (MS) is a chronic inflammatory disease that results in demyelination and degeneration of axons in the central nervous system (CNS). Disruption of the blood-brain barrier (BBB) occurs at an early stage of MS and in the animal model experimental autoimmune encephalomyelitis (EAE) and is central to the initiation

and maintenance of MS pathogenesis by permitting leukocyte infiltration into the CNS. Recently, we made the important discovery that when applied to pre-existing EAE disease, chronic mild hypoxia (CMH; 10% O2) markedly accelerates neurological recovery, leading to long-term stable reductions in disability score.

Histologically, this protection correlated with reduced levels of vascular disruption and leukocyte accumulation and faster remyelination. Mechanistically, CMH promoted a vigorous angiogenic response and increased endothelial expression of tight junction proteins while reducing VCAM-1 expression, key indicators of enhanced

vascular integrity. In addition, CMH greatly enhanced apoptotic removal of infiltrated monocytes during disease remission. Having recently found that hypoxia mimetics (HMs), drugs that stimulate hypoxia signaling pathways, also accelerate neurological recovery from EAE, we now plan to extend these studies in two ways. First, by

defining a HM treatment protocol that optimizes recovery from EAE. Second, define mechanistically how hypoxia inducible factor (HIF)-mediated vascular remodeling and apoptosis of infiltrated monocytes contribute to this protection. As MS onset typically occurs in young to middle-aged patients, we will study these events

both in young (10 weeks) and mature (8 months) mice. The goal of this proposal is to test the hypothesis that HMs promote recovery from inflammatory demyelinating disease by enhancing vascular integrity and suppressing neuroinflammation via HIF-mediated signaling. Our hypothesis will be tested in three specific aims: (1) define a HM protocol that optimizes recovery from

EAE, (2) evaluate the contribution of vascular remodeling to the hypoxia protective response in EAE, and (3) evaluate the contribution of monocyte apoptosis to the hypoxia protective response in EAE. Building on our fundamental observation that CMH accelerates recovery from EAE and that the HM drug FG-4592 exerts similar protection, both in the relapsing-remitting and chronic progressive EAE models, we now

plan to evaluate the translational potential of these findings by (i) defining an optimal FG-4592 treatment protocol and (ii) define mechanistically how HIF-mediated vascular remodeling and apoptosis of infiltrated monocytes contribute to this protection. Successful completion of these studies will further our goal of developing this

approach as a novel treatment for MS.