Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) whose cause is not known. The majority of the disease symptoms and disability that are observed in MS are thought, however, to be the end result of the infiltration into the CNS of a large number of white blood cells. Although quite a few drugs are available to treat MS, they do not work all of the time in everyone, and over time most people get worse and suffer from increased disability. This suggests that these medications are not sufficiently protecting the CNS and are failing to stimulate repair of these damaged areas. Because of this, we are still searching for a "complete" therapy for MS, one that will stop patients getting worse and protect the CNS from the damage that is caused in MS or one that will repair the damage that has already occurred.
The renin-angiotensin-system (RAS) is a peptide hormone system that regulates blood pressure and water balance. Recently however, RAS has been shown to have some function in the CNS and in neurological disease. RAS exists as a balance between two distinct axes that counter-regulate each other: a blood vessel constricting, pro-inflammatory axis and a blood vessel dilating, anti-inflammatory axis. There is increasing evidence that the pro-inflammatory axis of RAS in upregulated in the CNS of MS patients while there are decreases in anti-inflammatory axis. These observations, and our preliminary data, suggest that components of the RAS pathway in the CNS are indeed an integral part of the disease processes involved in MS, and we propose to investigate this further. We hypothesize that there is an imbalance in the anti-inflammatory axis of RAS in the CNS of MS, and animal models of MS, to such a degree that it significantly contributes to the disease pathology. We also wish to test if treatment with A(1-7), a specific component of the anti-inflammatory axis, will correct this imbalance. A(1-7) has been shown to directly affect immune regulation, wound healing, and stem cell mobilization, and it counteracts the effects of angiotensin II (a member of the pro-inflammatory axis).
To fully test our hypothesis, we propose to carry out two specific aims. The first will assess changes in the two arms of RAS at distinct stages of disease using both brain tissue collected post-mortem from patients with MS and also by using animal models of disease. This will give us a large amount of data describing those components of the RAS that are altered the most during disease. In Specific Aim 2, we will determine if treatment with A(1-7) helps the disease using an animal model of MS. In our preliminary studies using small numbers of animals, treatment after the first symptoms were observed appeared to help: treated mice did not progress as rapidly and had a less severe disease than untreated mice.
This research is directly applicable to all patients with MS. Sadly, the current prognosis for MS patients as their disease progresses is quite poor, with a limited number of therapies and none demonstrating any significant delay in neurodegenerative decline. We believe that by tilting the axis of RAS in favor of the protective arm, we will not only halt the inflammatory cascade of events in MS, but may also offer protection of the CNS and even promote repair. Thus, we feel that treatment with A(1-7) has the potential to be a significant improvement over all of the current therapies available to MS patients, and one that may open up therapeutic avenues to MS patients with progressive disease. With appropriate preliminary data, as will be collected in the proposed study, we should be successful in attracting significant and sustained funding, either from government entities or from foundations or private investment that would enable us to assess the utility of using this compound to treat MS. Given that our preliminary data suggest that treatment with A(1-7) peptide reduces disease severity, we feel that this is a readily achievable objective. Furthermore, as A(1-7) is already in clinical development (through Phase II and III) in humans for other indications, there will be little obstacle to initiation of clinical trials in MS. The pharmaceutical formulation of A(1-7) has already demonstrated favorable outcomes in multiple clinical trials, with a safe profile, and is well tolerated (over 200 patients have been exposed without serious adverse events). Thus, should our preliminary observations be confirmed in the more rigorous testing we have proposed here, we expect that it would not take long for this drug to be brought to trial.