Development of Novel Metformin Analog for Treatment of Parkinson's Disease

ABSTRACT of SBIR PproposalRNSFunded SepMore than a million Americans are afflicted with Parkinson s diseasePDa debilitating neurodegenerative disorderAs a result of a progressive and substantial loss of dopaminergic neurons in the substantia nigra compactaPD patients suffer from severe neurological deficits that can become incapacitating withinyears of diagnosisExisting PD treatments focus on alleviating motor symptoms by compensating for neurochemical deficitsbut such treatment fails to halt the progression of the diseaseThe discouraging lack of effective neuroprotective drugs is primarily attributed to a limited understanding of the complex mechanisms underlying the degeneration of the nigral dopaminergic systemandalthough mitochondrial dysfunction is recognized as the overriding pathophysiological hallmark of PDno effective treatment options are available to improve mitochondrial functionMetforminMetan FDA approved anti diabetic drug with an extraordinary safety profilewas recently found to influence metabolic and cellular processes associated with aging and the development of neurodegenerative diseaseUnfortunatelythe potential utility of Met as a mitochondria targeting therapeutic is limited by the drug s chemical properties at physiological pH where it exists as a hydrophilic cation that enters mitochondria rather inefficientlyNotablyour research team was able to increase the mitochondrial concentration of Mettofold by attaching a lipophilic cationtriphenyl phosphoniumTPPThe novel compounda mitochondria targeted metformin called MitoMetis a promising candidate for a drug development program focused on generating treatments for aging related disorders and diseases attributable to mitochondrial dysfunctionOur preliminary studies revealed two exciting properties of MitoMetIt is brain bioavailable and it leads to substantially higher mitochondrial biogenesisandgtfoldthan unmodified Met in cell culture and animal model studiesThusthe overarching hypothesis of our SBIR Phase I proposal is that our Met analogMitoMetwill provide neuroprotective benefit for treatment of Parkinson s disease due to its ability to activate a bioenergy sensingsurvival signaling pathwayPKDAMPKthat regulates mitochondrial biogenesisThis PhaseSBIR proposal will pursue two specific aims designed to test this hypothesisIn Aimwe will perform detailed pharmacokinetic and target engagement studies to determine the appropriate dosedosing intervalsand pharmacological properties of MitoMetthese will serve as the foundation for detailedin vivoefficacy studiespreclinicalto be conducted in PhaseIn Aimwe will perform a trio of studies to further assess the drug like properties of MitoMet metabolite stabilityPharma ADME fingerprint and repeat dose toxicologyIn terms of the overall impact of our studieswe expect to improve the quality of life for PD patients by developing a therapeutic that improves mitochondrial functionNotablythe high safety profile of the FDA approved parent moleculeMetforminshould facilitate our ability to bring this novel neuro restorative drug to market more quickly NARRATIVE Mitochondrial defects have been implicated in the pathogenesis of Parkinson s diseasebut no treatment is currently available to improve the efficiency of dysfunctional mitochondria in PDThe main goal of this proposal is to determine the drug like properties of MitoMet with favorable PK PD profile for further development of this class of compound in preclinical animal modelsIt is anticipated our unique mitochondrial targeted strategy will ultimately lead to the development of better therapeutic agents for the treatment of PD