ROAD TO THE CURE UPDATE JUNE 2013

The month of May was a very busy month for the SDBC in that we moved our vivarium to our new facility.

Our efforts in generating a colony of Alpha-Synuclein and LRRK2 Transgenic Mice have begun to bear fruit. Alpha-syn and LRRK2 breeding pairs have begun to produce pups. The process of genotyping these pups to determine which ones have inherited the alpha-syn or LRRK2 allele (forms of the same gene) from their parents has begun; Using molecular tools such as polymerase chain reaction (PCR) to analyze tiny amounts of DNA from these pups to assess their genetic makeup. Pups who have acquired the alpha-syn or LRRK2 allele will be used in the study to evaluate the effect of our drugs on Parkinson’s disease. This process requires we generate nearly 90 alpha-syn and 90 LRRK2 transgenic mice to begin our experimentation in collaboration with van Andel Institute in Michigan. The process is time consuming and expensive, but very achievable.

Mutant LRRK2 Antagonist. LRRK2 is a multi-domain protein bearing kinase activity. Mutations in this gene have been associated with Parkinson’s disease. Specifically, G2019S mutation leads to an increase in LRRK2 kinase activity correlating with the manifestation of disease. It is now believed that LRRK2(G2019S) over-expression results in neuronal death. Thus, recently, LRRK2 has been identified as one of the key therapeutic targets for Parkinson’s disease. As a result, there are numerous research groups all over the globe trying to develop inhibitors for the kinase activity of mutant LRRK2. There are two basic approaches being pursued. The pros and cons of these approaches are described below:

Small molecule approach

- High blood-brain barrier (BBB) permeability

(very desirable feature)

- Low manufacturing cost (makes it affordable)

- Lack of specificity (Lack of specific target sites on proteins)

- Frequent dosing

- Temporary relief of symptoms and stops working after some

time

- Does not cure the disease

ii. Macromolecules (Classical antibodies approach)

- High specificity (very desirable)

- Poor BBB and tumor penetration

- Toxicity

- Targets single antigens

- Cost

Any therapeutic approach for neurodegenerative disorders must permit non-invasive delivery of drugs to the central nervous system (CNS). Thus far, the colossal failure of government, private research and the pharmaceutical industry to develop therapy for brain diseases has been due to the inability to breach the BBB non-invasively.

The SDBC has been following a unique approach, which overcomes limitations of “Small and Macromolecule Approaches”. Its molecular approach is known as SMART™ Molecule (SM) approach (SMART stands for Specific Molecular Architecture for Recognition and Therapy). These SMs have been already shown to penetrate the BBB into the central nervous system where they bind to their targets with high specificity and stay in the blood for at least 7 days. In preliminary studies, mice treated for 42 days did not show any toxicity. Thus, these SMs appear to be ideal therapeutic candidates. The SDBC is talking to some pharmaceutical companies for help to bring these SMs from the bench to the bedside.

Mutant-LLRK2 SMART™ Molecule. The SDBC has isolated and purified a small quantity of mutant-LRRK2-SM. Until the SDBC can afford to buy the full length mutant LRRK2 protein for generating an affinity column, the SDBC scientists tested their luck by developing a small segment of the full length protein to generate an affinity purification media. This small segment (aka: peptide) was used to isolate and purify mutant LRRK2 SMART molecule (an antagonist). Thus, SDBC has generated about 100 ug of the Mutant-LRRK2-SM and now planning experiments with the mutant-LRRK2-SM.

Parkinson’s Resource Organization is appreciative to have been the first Parkinson’s Organization to have been introduced to this life-changing science. It needs funding to bring it to fruition.

Being a part of this historic, humanitarian effort requires an investment. If you have Parkinson’s it may be an investment into your life, if you don’t have Parkinson’s it may be an investment in humanity. You will be introduced to the right parties for making your investment possible. The only impediment to getting to the human side of this science is funding. The sooner the funds are raised the sooner human clinical trials can begin. If funding had happened a year ago January this science would probably be at or nearing human clinical trials today. If funding happens a year from now, you might expect clinical trials two years from now. It’s all in the funding.