Details

Project TitlePAD Inhibitors for Treatment of Multiple Sclerosis
Track Code11047
Short Description

Small molecule inhibitors of protein arginine deiminases (PAD) for treatment of multiple sclerosis and other neurodegenerative disorders


 
Abstract

Multiple sclerosis is a neurodegenerative condition that results in cognitive and physical disability and shortened life expectancy that affects more than 2.5 million people globally.  MS is the most common demyelinating neurodegenerative disease.


Current therapies for MS do not delay the progression of, or support the reversal of the disease.   The majority of these therapies are immune modulators that aim to treat the symptoms of the disease and decrease both the severity and frequency of disease relapses. The side effects associated with the use of immune modulators include increased risk for infection and higher rates of cancer. Treatments with a novel mode of action that are able to delay the development and reverse the disease are needed.

Dr Lakshmi Kotra at UHN has developed two series of molecules that target PAD2 and PAD4 enzymes activities, thus inhibiting excessive citrullination of the myelin basic protein, a process that has been shown to destabilize the myelin sheath and trigger a pathologic autoimmune response that leads to MS.

 

Two compounds have shown good inhibition of PAD isozymes in vitro and in the EAE mouse model of MS in vivo. Further experiments suggested that one of these compounds, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependent efficacy in the EAE mouse model and in the cuprizone-mediated demyelination model.

         

Molecule will target PAD2 and PAD4 enzymes activities, thus inhibiting excessive citrullination of the myelin basic protein, a process that has been shown to destabilize the myelin sheath and trigger a pathologic autoimmune response that leads to MS.

        

EAE progression in mice treated with PBS or PAD inhibitors. EAE was induced in female C57BL/6 mice with MOG35-55/CFA plus pertussis toxin. Mice were followed daily for the development of clinical signs. Shown are clinical scores ± SEM over time after immunization (A) and after initiation of the treatment (B).  From Bioorg. & Med. Chem. 25: 2643-2656 2017

 
 
Tagstherapeutics, small molecule, Parkinson's disease, other neurodegenerative diseases, PAD Inhibitor, PAD2 Inhibitor, PAD4 Inhibitor, demyelination, Myelin, citrulline, citrullination, TGHRI, PAD INHIBITORS FOR TREATMENT OF MULTIPLE SCLEROSIS, multiple sclerosis, alzheimer's disease
 
Posted DateJun 13, 2017 5:46 PM

Potential Applications

  • A first-in-class,  small-molecule therapy for multiple sclerosis
  • Therapy for other neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease

Principal Investigator

Dr. Lakshmi P. Kotra, University Health Network

Project Status

Pre-clinical development

Patent Status

Two patent families:

  • PCT/CA2013/050597 (national Phase entry in US, EU and CA)
  • US62/205,939

Partnering Opportunity

Available for licensing/development partnership on an exclusive basis

Publications

For Further Information, Please Contact:

Thomas Parsons M.Sc., CLP | Licensing and Commercialization Professional | Technology Development and Commercialization | University Health Network | +1 416 581-7403 | tparsons@uhnresearch.ca

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