PAD Inhibitors for Treatment of Multiple Sclerosis
- Technology Application
- A first-in-class, small-molecule therapy for multiple sclerosisTherapy for other neurodegenerative diseasessuch as Alzheimer’s disease and Parkinson’s disease
- Detailed Technology Description
- Small molecule inhibitors of protein argininedeiminases (PAD) for treatment of multiple sclerosis and other neurodegenerativedisorders
- *Abstract
-
Multiplesclerosis is a neurodegenerative condition that results in cognitive andphysical disability and shortened life expectancy that affects more than 2.5million people globally. MS is the mostcommon demyelinating neurodegenerative disease.
Currenttherapies for MS do not delay the progression of, or support the reversal ofthe disease. The majority of thesetherapies are immune modulators that aim to treat the symptoms of the diseaseand decrease both the severity and frequency of disease relapses. The sideeffects associated with the use of immune modulators include increased risk forinfection and higher rates of cancer. Treatments with a novel mode of actionthat 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 andPAD4 enzymes activities, thus inhibiting excessive citrullination of the myelinbasic protein, a process that has been shown to destabilize the myelin sheathand trigger a pathologic autoimmune response that leads to MS.
Twocompounds have shown good inhibition of PAD isozymes in vitro and in the EAEmouse model of MS in vivo. Further experiments suggested that one of thesecompounds, a non-covalent inhibitor of PAD2 and PAD4, exhibits dose-dependentefficacy in the EAE mouse model and in the cuprizone-mediated demyelinationmodel.Molecule will target PAD2 and PAD4 enzymesactivities, thus inhibiting excessive citrullination of the myelin basicprotein, a process that has been shown to destabilize the myelin sheath andtrigger a pathologic autoimmune response that leads to MS.
EAE progression in mice treated with PBS orPAD inhibitors. EAE was induced in female C57BL/6 mice with MOG35-55/CFA pluspertussis toxin. Mice were followed daily for the development of clinicalsigns. Shown are clinical scores ± SEM over time after immunization (A) andafter initiation of the treatment (B). FromBioorg. & Med. Chem. 25: 2643-2656 2017
- *Principal Investigator
-
Dr. Lakshmi P.Kotra, University Health Network
- *Publications
- Sarswat A, et al. (2017). Inhibitors of protein arginine deiminases and theirefficacy in animal modelsof multiple sclerosis. Bioorg. Med.Chem. 25:2643-2656.
- Country/Region
- USA
