Lipidated Stable BAM8-22 Offers a Promising Therapeutic for Neuropathic Pain

DESCRIPTION provided by applicant Neuropathic pain is a serious health problem that affects millions of people worldwide and occurs in as much as of the general population The management of neuropathic pain in patients is complex with an estimated of individuals refractory to existing analgesic therapies The aging population the diabetes epidemic and the significant cohorts of cancer and AIDS patients all contribute to the prevalence of intractable neuropathic pain The large number of affected individuals highlights the pressing need to develop novel therapeutics for this condition The Mrgpr Mrg SNSR family of G protein coupled receptors GPCRs are expressed in the dorsal root ganglia and play an important role in the modulation of nociception Intrathecal administration of the endogenous peptide BAM attenuates neuropathic pain in rodent models through activation of the human MrgprX ortholog mouse MrgprC rat MrgprC The therapeutic effects however are short lived On Target Therapeutics has championed a novel technology to develop stable long acting peptide modulators of GPCRs These analogs are peptide linker lipid conjugates that are membrane anchored to provide local activity with high potency and long term stability We have modified endogenous BAM to generate a higher potency analog that anchors into the cellular membrane and provides local activity In Aim we propose to generate more stable analogs by modifying specific amino acids that we have already identified In Aim these andapos lipidated stable BAMandapos constructs will be tested in a mouse model of neuropathic pain chronic constriction injury Completion of these Specific Aims will result in th selection of a well characterized candidate compound for further development Phase II studies will focus on toxicology dosing mode of administration and testing of the stable BAM analog in a larger animal model The Phase I efforts will be performed at On Target Therapeutics in conjunction with our research partners at Tufts Medical Center Dr Alan Kopin and Johns Hopkins University Dr Xinzhong Dong

PUBLIC HEALTH RELEVANCE Neuropathic pain affects millions of people worldwide and remains a serious unmet medical need A significant fraction of patients receive little or no relie from existing therapies The successful development of our candidate compound will provide a novel treatment option for individuals suffering from neuropathic pain