The connection between genetic mutations in the GCase enzyme and Parkinson's disease goes beyond Gaucher's Disease. The risk of developing Parkinson's disease (PD) in the broader population has been firmly linked to GCase mutations (Sidransky and Lopez, 2012). At the biochemical level, reduced GCase activity in the brain is correlated with synuclein accumulation and increased PD risk (Sidransky and Lopez, 2012). For example, the risk of PD in Gaucher patients, who have 5-25% normal GCase activity, is ~20-fold higher compared to the general population, while the risk of PD in carriers of the GCase mutations, who have 50-90% normal GCase activity, is 5-8 fold increased.
It follows that increasing GCase activity in both Gaucher patients and mutant-GCase carriers could significantly decrease PD risk and possibly the rate of disease progression. Recently, data have emerged suggesting that GCase levels are also low in idiopathic PD patients with two normal GCase alleles (Gegg et al, 2012). Building on these findings, researchers at the National Human Genome Research Institute have developed models of macrophages, the cells that use GCase to break down lipids, of Gaucher disease that will help facilitate future drug development efforts (Aflaki et al, 2014). LTI's lead program is focused on developing GCase agonists to treat PD for both the Gaucher and common PD community.
The lysosome functions as a processing center in human cells, breaking down proteins into their building blocks. When errors occur in the enzymes used in this processing center, build-up of unwanted proteins occur resulting in cellular damage. A set of genetic diseases, called Lysosomal Storage Disorders, are the result of genetic mutations in different lysosomal enzymes. Gaucher Disease, a lysosomal storage disorder, is the result of homozygous mutations in the glucocerebrosidase (GCase) gene (also known as GBA1). People diagnosed with Gaucher disease have a build-up of a lipid (gloucosylceramide) in their cells, causing serious health issues, including a higher incidence of neurodegenerative diseases such as Parkinson's. Many other lysosomal storage disorders carry this similar profile: genetic mutations lead to loss of enzyme function, build up of unwanted proteins, and the long term development of neurodegenerative disease. At LTI, we are leveraging our world-class expertise in lysosomal storage biology to tap into genetic association between lysosomal storage diseases and neurodegeneration to develop novel therapeutics.
LTI is leveraging its expertise in lysosomal biology to develop novel small molecules to be used in the treatment of various neurodegenerative diseases. Our lead program, the GCase agonist, has its foundation in a small molecule GCase activator discovered by the National Institute of Health. LTI has the exclusive license to this intellectual property. This lead will be optimized to identify a clinical candidate. We are currently improving upon the pharmacological parameters of this molecule and advancing toward lead identification. With the help of a grant from The Michael J. Fox Foundation, LTI is also studying GCase as a biomarker, to be used for identifying Parkinson's disease patients likely to respond to our therapeutic drug candidates. Additionally, LTI is expanding its research into additional lysosomal enzyme deficiencies, unlocking the true potential of our discovery platform.