Aeolus Pipeline Initiative: Parkinson's Disease

Third party scientific collaboration with University of Colorado.
Parkinson’s disease is a common neurodegenerative disorder, second in frequency only to Alzheimer’s disease. Parkinson’s affects approximately 500,000 Americans, with an incidence ranging from 14 to 80 per 100,000. Every year about 50,000 new cases are diagnosed in the United States. It is found in about 1% of those older than 50 years and 3% of those aged 95 or greater. According to the National Parkinson Foundation, each patient spends an average of $2,500 a year for medications. After factoring in office visits, Social Security payments, nursing home expenditures, and lost income, the total cost to the Nation is estimated to exceed $5.6 billion annually.

Parkinson’s specifically involves the progressive destruction of the nerves that secrete dopamine and control the basal ganglia, an area of the brain involved in the regulation of movement. Dopamine turnover has been shown to elevate the levels of ROS in the brain. In addition, a street-drug contaminant has appeared that can cause parkinsonism in drug abusers. The compound N-methyl-4-phenyl-1, 2, 3, 6tetrahydropyridine, or MPTP has been identified in underground laboratory preparations of a potent analog of meperidine (Demerol). MPTP-containing powder, sometimes sold as a new “synthetic heroin,” can be dissolved in water and administered intravenously or taken by the intranasal route. MPTP has been documented to produce irreversible chronic parkinson symptoms in drug abusers. Agents such as MPTP overproduce ROS in the basal ganglia. Therefore, ROS mediated neuronal dysfunction may play a key role in the development of Parkinson’s disease. Symptoms of this disease include tremors, rigidity, and bradykinesia (i.e. slowness of movement). In the more advanced stages, it can cause fluctuations in motor function, sleep problems, and various neuro-psychiatric disorders.

A goal for this preclinical program is to identify additional manganese porphyrins from Aeolus’ compound library that have enhanced pharmaceutical profiles for use in neurodegenerative diseases. The Company is focusing these efforts on its AEOL-112 series (which all contain the same core structure noted above) that are smaller, more lipophilic and lack mutagenicity in the Ames test. Preliminary studies have found that these compounds penetrate the blood brain-barrier better than compounds from the Company’s AEOL-101 series and offer some protection in an MPTP-animal model of Parkinson’s disease. Because MPTP is redox active agent that destroys striatal neurons that produce dopamine, it is an often used-agent of Parkinson’s disease in animal models of the disease. Striatal dopamine (DA) levels, a good measure of MPTP neurotoxicity, were assessed by HPLC-EC following administration of mice with MPTP (15 mg/kg x 3, s.c., 24h intervals). MPTP-induced DA depletion was partially attenuated by AEOL 11207 administration (15 mg x 5, s.c., 24h. intervals). Current studies are underway to screen the 112 series of manganese porphyrins for a lead candidate to move forward in this clinical indication.