Parkinson's Disease (PD) is the most common motor disorder affecting the elderly. In the U.S., approximately 50,000 new cases are diagnosed each year, with approximately 500,000 Americans affected at any given time. It is expected that the number of cases of PD will double in the next ten years, mirroring the aging of the U.S. population.
PD is a progressive neurodegenerative disease caused by loss of neurons in the nigrostriatal area of the brain that normally produces dopamine. Dopamine, a chemical messenger, is responsible for signal transduction between the substantia nigra and the corpus striatum. Loss of dopaminergic neurons results in a decrease in dopamine concentration. In the absence of dopamine, the nerve cells of the striatum fire out of control, leaving affected individuals unable to control their movements in a normal manner. Greater than 80% of dopaminergic neurons may be lost in PD patients.
The sources of this neuronal loss remain elusive. However, research has pointed to several potential causes including oxidative damage, environmental factors (e.g. pesticides, chemical toxins), and genetic predisposition. It is likely that a combination of these factors may be important in the etiology of PD.
Current therapies for PD are directed towards alleviating the associated symptoms, and have little or no effect on halting or even slowing disease progression. Furthermore, such therapies often become ineffective as the disease progresses. As such, drugs that can slow or stop disease progression will be of great importance in meeting this as yet unmet medical need.
PARKINSON'S DISEASE ETIOLOGY
Degenerating neurons in PD contain intracellular inclusions termed Lewy bodies, which are composed of a dense core of filamentous and granular material consisting primarily of protein oligomers. The protein α-synuclein has been identified as the major component of Lewy bodies and also is linked to several other forms of neurodegenerative disease including Alzheimer's Disease, diffuse Lewy body disease, multiple systems atrophy, and amyotrophic lateral sclerosis or ALS. Like many other proteins involved in neurodegenerative disease, α-synuclein has a high propensity to oligomerize or aggregate, forming the large protein fibrils that are deposited in Lewy bodies.
Three lines of evidence implicate α-synuclein oligomerization as having a causal role in Lewy body formation and thus PD:
- two mutant forms of α-synuclein that have been linked to familial PD have been shown to induce a more rapid oligomerization of the protein
- over-expression of α-synuclein in neuronal cell lines in culture leads to the formation of intracellular Lewy body-like inclusions and to cellular injury
- transgenic mice and drosophila engineered to express wild type or mutant forms of human α-synuclein develop Parkinson's-like disease
The mechanism through which α-synuclein oligomers/fibrils lead to neuronal death remains unclear. However, there is circumstantial evidence that a-synuclein oligomers may induce mitochondrial dysfunction and, in turn, might lead to cell death.
The Company's PD Program is directed towards the identification and development of novel compounds that can inhibit the oligomerization or aggregation of the α-synuclein protein. As described above, several lines of evidence suggest that α-synuclein oligomerization is a direct cause of Parkinson's-associated pathology and disease etiology. Panacea believes that inhibitors of α-synuclein oligomerization may block the formation of Lewy bodies and slow further neurodegeneration. As PD is a progressive neurodegenerative disorder, even a relatively minor inhibition of neurodegeneration should result in a dramatic slowing of disease progression.
