Cathepsin S inhibition and diabetic neuropathy
Peripheral neuropathy is the most common complication of diabetes and will afflict over half of the 25 million Americans who currently suffer from the disease. There is no FDA-approved therapy to prevent distal degenerative neuropathy neuropathy or reverse the neuropathy that is already present in many newly diagnosed diabetic patients and which gets progressively worse over time. There is therefore a need to evaluate novel therapeutic approaches in preclinical studies with the anticipation that demonstration of efficacy will prompt clinical trials. To this end, we have begun to investigate the potential role of diabetes-induced increased expression of the enzyme cathepsin S and the subsequent increase in active fractalkine on indices of neuropathy. Our preliminary data demonstrates that diabetic rodents show increased tissue expression of cathepsin S and increased fractalkine levels in the plasma. Blocking cathepsin S activity using a highly selective inhibitor acutely relieves behavioral indices of pain in rodent models of neuropathy induced by either paclitaxel or diabetes, making cathepsin S inhibitors a promising therapy for painful neuropathy. During these initial studies we also noted that repeated administration of a cathepsin S inhibitors over many days leads to amelioration of pain that persists well beyond the effective life of the drug and indeed for many weeks after drug withdrawal. This leads us to propose that cathepsin S inhibition not only acutely ameliorates pain but also has the capacity to be disease modifying. We therefore propose to perform a pilot study in which diabetic rodents are treated with a cathepsin S inhibitor and the onset and progression of behavioral, functional and structural indices of peripheral neuropathy is followed in order to determine whether the treatment can prevent and reverse indices of degenerative neuropathy. Our intent in performing this pilot study is to illustrate the therapeutic potential of cathepsin S inhibition with the goal of prompting the further preclinical, and ultimately clinical, development of cathepsin S inhibitors as a treatment for diabetic degenerative neuropathy.

Detecting diabetic neuropathy in rodents by imaging corneal nerves
Visualization of corneal nerves by confocal microscopy is currently being developed as a sensitive and completely non-invasive method of detecting neuropathy in diabetic patients that allows the repeated measurements necessary for longitudinal studies of drug efficacy. Corneal confocal microscopy (CCM) has been applied to live rodents and other species and our exploratory studies indicate that corneal nerves can also be visualized ex vivo. In the proposal we will establish optimal conditions for visualizing and quantifying corneal nerves in rats and mice in vivo and in eyes from rats ex vivo. Once these conditions are established, we will use CCM to detect neuropathy in eyes of control and diabetic mice provided from new models of diabetes developed by the AMDCC. We will also compare the structural neuropathy detected by CCM with the current methods of phenotyping neuropathy in tissues from these animals which are reduced axonal calibre in the sciatic nerve and loss of intraepidermal nerve fibers in the paw skin. The sensitivity of CCM to detect onset and progression of neuropathy in a longitudinal study of the eyes of mouse models of type 1 and type 2 diabetes will also be studied and compared with onset and progression of nerve conduction velocity slowing and paw thermal hypoalgesia. The purpose of these studies is to establish the viability of CCM as a sensitive means of detecting neuropathy in diabetic rodents so that it can be used to phenotype new models of diabetes being developed by the AMDCC and to allow assessment of the efficacy of new therapeutics in rodent models prior to clinical trials using the same end point and equipment.

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