CRP pre-clinical research – latest update (May 22nd, 2020)
CRP Peptide therapy research project for chronic spinal cord injury repair
Background information: The formation of an enduring glial scar near the injured site leads to poor nerve regrowth capacity and poor functional outcomes in chronic stages after SCI. Chondroitin Sulfate Proteoglycans (CSPGs) are the major components of this glial scar. The small peptide (a tiny organic compound) called CSPG Reduction Peptide (CRP) was designed by Dr. Yu Shang Lee’s lab (Cleveland Clinic – USA) to meet this need. The endParalysis started to support the translation of this potential therapy from the lab to the clinics (i.e. to humans) in 2018. The non-invasive character of the CRP (it can be applied by subcutaneous injection) is of great interest. CRP treatment, if proven effective, will, in principle, be easily applied to human patients and might constitute a very valuable alternative to other scar-alleviating therapies currently under development such as Ch’ase. Indeed, the latter treatment requires a specific and elaborate delivery method to safeguard its effectiveness as well as safety for the patient.
Latest update (May 2020): Further to the ongoing the CRP technology development since 2013, Dr. Yu Shang Lee’s lab carried out additional studies using a combinatory strategy of both CRP and ISP to treat T8 chronic contusion SCI, as of August 2018. The project, co-funded by the endParalysis foundation, aimed to determine the efficacy of CRP alone, of ISP alone, and of CRP + ISP (ISP is another peptide, developed in Dr. Jerry Silver’s lab, Case Western Reserve University). Starting two-month post-SCI, the treated animals received the various peptides by daily subcutaneous injection during three consecutive months. Both CRP and ISP are administered at a low dose in this study.
Furthermore, at the end of 2019, endParalysis allocated 34K€ for the next step of the CRP study, mainly testing dose responses of CRP to see if a higher dose can lead to an additional functional improvement, after chronic spinal cord injury. This study had started in Dr. Lee’s lab but had to be (temporarily) suspended because of COVID-19 lockdown measures. We expect the study to restart early June 2020.
Results so far: 2018-2019 study: The behavioural testing showed an overall improvement in locomotor and bladder function in the CRP-treated animals. While there was a trend showing CRP+ISP works slightly better in improving BBB scores (testing stepping function) than CRP alone, there was, overall, no significant difference between the CRP+ISP and CRP groups. Importantly, both CRP and CRP+ISP groups demonstrated better hind limb/forelimb coordination). The study seems to show that CRP enhanced connectivity established across injury site and nerve sprouting below the injured site after treatment, as well as an improved function for both locomotion and bladder (the CRP-treated groups show less hyperactivity, better void efficiency, and lower voiding pressures).
Finally, the anatomical findings also correlated with the functional outcomes. Firstly, the CRP-treated animals showed reduced CSPGs near the injury site. Secondly, regrowth of serotonergic (5-HT) fibers at the injured site and sprouting below the injured site (lumbar segments) were shown. These suggest that modulating inhibitory proteoglycans with CRP and CRP+ISP may increase neuroplasticity, thereby contributing to behavioral recovery after chronic T8 contusive SCI.
Next steps:
– We hope to receive the first results of the 2020 CRP dosing study funded by endParalysis by the end of 2020
– Meanwhile, Dr. Yu-Shang Lee is working with Dr. Brian Kwon to investigate the efficacy of CRP in a large animal model using minipigs T10 subacute stage injury model to test both locomotion and bladder function. The study progress has also been delayed by COVID-19
– Next step for the CRP therapy will be conducting Pharmacokinetics and Safety/toxicity tests of CRP. Those are necessary for any therapy to go to spinal cord injury clinical trials.