Diabetic peripheral neuropathy (DPN) is one of the most common and devastating complications of diabetes mellitus, affecting more than 50% of diabetic patients, and is the leading cause of foot amputation. DPN, characterized by peripheral axonal degeneration and demyelination, can be disabling and extremely painful, causing significant loss of functional abilities and decreasing quality of life. Currently, the only effectve treatments are glucose control and pain management. Although glucose control and some preventive strategies have been proposed to attenuate the development of DPN, none of them has demonstrated neuroreparative activity for existing neuropathy. Therefore, a neurorestorative strategy to repair damaged peripheral nerves is still critically needed to alleviate the persistent symptoms of established DPN. Cognosci has innovatively created and characterized a series of peptides derived from human apolipoprotein E (apoE), which we designate as "COG" compounds, from which we have identified a lead compound COG112 for inflammatory neurodegenerative diseases. Extensive studies have demonstrated that COG112 and other COG compounds exert potent neuroprotective activities against oxidative stress and inflammatory response, as well as neuroreparative activities both in vitro and in vivo. We have also obtained data showing that COG112 can significantly prevent axonal degeneration and promote axonal regeneration and remyelination in a sciatic nerve crush model. A similar neuroprotective effect has been validated in animal models of a variety of neurological disorders such as traumatic brain injury, spinal cord injury, subarachnoid hemorrhage and multiple sclerosis, implicating a therapeutic efficacy for these diseases. Because apoE has been considered as one of the genetic factors of diabetes and DPN, our preliminary data support that COG112 may demonstrate therapeutic efficacy on DPN by protecting peripheral nerves from hyperglycemia-mediated oxidative and inflammatory damages and promoting neuroregeneration. Therefore, we will test our hypothesis through both in vitro and in vivo models of DPN in the following specific aims: 1) To validate the potential neuroprotective effect of COG112 on a high glucose-induced neuronal death and axonal damage in primary dorsal root ganglion (DRG) cultures and the neuroregenerative effect on neurite outgrowth of DRGs from adult streptozocin (STZ)-induced diabetic rats. 2) To determine if COG112 exerts neuroprotective and neurorestorative effects in vivo by functional and histological examination in a DPN model of BKS db/db mice.
Our overall goal is to develop a novel neurorestorative therapy for diabetic neuropathy with not only protective potential, but also with reparative capability. Completion of this Phase I study will enable us to obtain proof of concept that apoE-mimetic COG112 can antagonize hyperglycemic oxidative stress, interfere with noxious inflammatory responses, and promote axonal regeneration to maximize functional recovery. If substantiated by this study, COG112 may represent a first-in-class neurorestorative therapy for diabetic peripheral neuropathy that can satisfy this critically unmet medical need. The strategy may potentially be useful for other complications of diabetes such as diabetic retinopathy.