claudin-1 modulatory peptide as adjuvant for improved local pain management
Bayerische Patentallianz GmbH
Effective pain management during trauma or orthopedic surgery of skeletal bones, joints and tendons as well as in post-operative treatment and rehabilitation support is essential for the patientÂÂÂs wellbeing and a quick and successful recovery. It also plays an important role in the context of chronic limb pain.
Commonly used treatment options exhibit a number of detrimental side effects. Available pain therapeutics such as local anesthetics also impair motor and sensory function and therefore hinder rehabilitation whilst systemically applied opioids can cause sedation, nausea and respiratory depression. Locally applied hydrophilic opioid drugs (such as DAMGO or morphine) on the other hand could offer pain relieve without interfering with other neuronal types and without the unwanted side effects on the central nervous system.
However, their use on nociceptive nerve fibers is currently prevented by the fact that they cannot pass the perineurial cell barrier around the peripheral nerve cells.
The permeability of the perineureum for hydrophilic drugs is regulated by transmembrane tight junction proteins such as occludin-like proteins, junctional adhesion molecules and claudins. One of the key regulatory proteins for paracellular tightness is claudin-1.
A new claudin-1 modulatory lead peptide (C1C2) for enhanced paracellular transport of hydrophilic pain therapeutics through the perineurial cell barrier of the peripheral nervous system has been developed.
The 29 AA peptide C1C2 is derived from an extracellular loop of claudin-1. In in vivo studies in the rat'ÂÂÂs sciatic nerve, the peptide has been shown to transiently improve the efficacy of locally applied opioid peptide DAMGO or morphine in a in a time and dose dependent manner. An increase in nociceptive thresholds in naïve rats as well as an analgesic effect in rats with hindpaw inflammation without motor impairment was observed 24h after administration of C1C2 + opioid and lasted for about 48h.
Accordingly, in vitro studies revealed a decreased protein expression and immunoreactivity of claudin-1 in the membrane of the perineurim 24h after local injection of C1C2. A similar decrease in the transcellular electrical resistance (TER; an indicator of perineurial cell barrier integrity) was detected 24h and more pronounced at 48h, but recovered at 72h post C1C2 treatment. The peptide has a half-time of roughly 12.5h in rat blood plasma and proteolytic degradation results in two main cleavage products. No change in nerve function of morphology was observed.
- This invention offers a novel option for pain treatment during and after surgery of the musculoskeletal system as well as in the rehabilitation phase with a greatly improved side effect profile.
- More than 30 million cases of fracture related injuries were reported in the USA alone in 2009. Roughly half (48.8%) required surgery or medical procedures. What is more, the trauma market expects a continuous annual growth of about 10-12% till 2014 (Pearl Driver Patients Database).
- In addition, there are roughly 358,000 hip replacements (2005) and around 600,000 knee replacements (2009) in the US per year. The knee and hip replacement market is expected to grow by a yearly rate of 11.9% (Datamonitor, American College of Rheumatology, Bharat Book Bureau).
A preclinical data set of immunohistochemistry, pharmacokinetics, neuronal toxicity and mode of action studies has been created and early proof of concept in vivo experiments have been conducted