Background info:

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 (August 2023):

- 2018-2019 rodent study, after a first preliminary small study with a limited number of rodents, Dr. Yu Shang Lee’s lab carried out additional studies using more rats with a T8 chronic contusion SCI.  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). Various tests were conducted, including a combination therapy. Starting two-month post-SCI, the treated animals received the various peptides by daily subcutaneous injection during three consecutive months. Both CRP and ISP were administered at a low dose in this study.

The study showed that:

• • CRP significantly improved bladder function and locomotor function (*)
  • The results were not much improved or changed when adding up ISP (**).
  • The test highlighted, on the other hand, that ISP alone did not enable any functional recovery of the rats at the CHRONIC stage (although it has been proven Dr. Jerry Silver’s lab to have a robust effect at the ACUTE stage).

(*) Abstract from the Lee lab’s report:”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)”

(**) Abstract from the Lee Lab’s report: “While there was a trend showing CRP+ISP works slightly better in improving BBB scores (BBB is a test of stepping function) than CRP alone, there was, overall, no significant difference between the CRP+ISP and CRP groups”.

- 2020-2022 dosing (rodent) study:  the CRP dosing study (funds pre-allocated by endParalysis at the end of 2019) has  mainly tested dose responses of CRP to see if a higher dose can lead to an additional functional improvement, after chronic spinal cord injury.  However, the preliminary progress report relates very encouraging results. 

Patient enrolment/clinical trials/ next translational steps:

– We hope to receive the final results of the 2020 CRP dosing animal study funded by endParalysis soon.

– Meanwhile, Dr. Yu-Shang Lee has been working with Dr. Brian Kwon to investigate the efficacy of CRP in a large animal model using mini-pigs (T10 subacute stage injury model) to test both locomotion and bladder function. The study progress has also been delayed by COVID-19. The result of this study is not known yet.  

– 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.

Background info:

The over-expression of FL2 (an inhibitory protein) after spinal cord injury results in inhibition to axon growth. Preclinical research suggests that siFi2 (a drug developed by the US biotechnology company MicroCures) can silence FL2 activity and thus trigger regeneration and reattachment of axons at the site of injury. This therapy is based on gene lock-down and enhances the body’s intrinsic healing processes. 

Latest update (August 2023):

Following the promising functional improvement observed in previous acute trials, we have asked MicroCures and USU Uniformed Services University of the health science - USA)* to test the siFi2 therapy in rats with chronic injuries (endParalysis foundation funded this project through a research grant in 2021).  This study had to re-started due to technical issues and is still ongoing. We hope to provide an update on the results by end 2023

Patient enrolment/clinical trials/next translational steps:

This study is still at pre-clinical (animal testing) stage. However, we consider it to be a very promising therapy. If proven effective at the chronic stage of spinal cord injury, it might be combined with other treatments. The most exciting feature observed in the acute rodent study was the ability to generate rebinding/ reattachment of axons, so that the messages from the brain can be transmitted again.

Background info:

Funds from endParalysis enabled a pilot collaboration between Dr. Murray Blackmore at Marquette University and Dr. Steve Perlmutter at Washington University to test a new gene therapy treatment for chronic spinal cord injury. The animal study, funded by the endParalysis foundation in 2020- 2021, aimed to advance the promising new gene therapy approach for improving axon growth after CHRONIC spinal cord injury. It is based on a recent discovery from Dr Blackmore’s lab that a combination of two transcription factors, Klf6 and Nr5a2 (KN), stimulates robust and highly reliable growth from corticospinal tract (CST) axons. The goal here was to push in the direction of translation by determining whether KN is similarly effective in a more chronic and clinically relevant model of spinal contusion in the laboratory of Steve Perlmutter at the University of Washington. For more info about the project and its selection, read this blog post.

Latest update (May 2022):

The treatment has shown promise in animal testing when applied acutely to a mild injury, raising the question of whether it could be similarly effective in more severe and chronic injuries. With support from endParalysis the Blackmore and Perlmutter performed a series of experiments to establish viral designs and surgical techniques to deliver the treatment to rats in the chronic stage of spinal cord injury. Using these pilot data the two labs were able to secure additional funding from the Craig H. Nielsen foundation for expanded testing of this approach to enhancing repair and functional recovery after chronic spinal cord injury.

This figure illustrates successful and widespread gene delivery to injured neurons when administered in the chronic injury condition. This is an important prerequisite for translational development of this approach.

Patient enrolment/clinical trials/next translational steps:

This therapy is still at pre-clinical stage. Various studies need to be conducted before it is tested on human subjects with a spinal cord injury. 

Background info:

PNNi refers to a molecule that is already on the market (used to treat a rare disease). It was recently tested by Dr Kwok / University of Leeds, as a potential therapy for spinal cord injury. In her animal studies, the drug has shown promising results when used at the acute (i.e. very early) stage of SCI. The molecule seems to neutralise  the PNN (PeriNeural Net)  as well as the scar, which both prevent nerves regrowth. The main advantage of this therapy, if results are confirmed and the side effects are manageable, is obviously a shorter path to the clinics, since the drug is already approved.

Latest update (August 2023):

PNNi dosing study (including chronic SCI) by the Kwok Lab: this study was co-funded by the endParalysis foundation (2020-2022) together with two other foundations, i.e. the Marina Romoli Onlus (Italy) and  Gusu2cure (USA). The purpose of the study was to check the efficacy of the treatment at the chronic stage of SCI, and to determine the minimum dosage needed to reach a significant level of functional recovery. The study has proven that the molecule does indeed enable a clear functional recovery level in rats, even long after their initial injury, which is a very good outcome. PNNi molecule is used to treat people with a rare-disease and is thus suitable for clinical use. However, the latest study also showed that the dosage needed to achieve significant functional recovery in rats is higher than the one currently authorized on the market. Before going to human trial for use in spinal cord injury, it is necessary to finetune the treatment, either by increasing its efficacy so that it can be made effective at the authorized dosage or by addressing concerns of potential side effects and gaining regulatory approval for use at higher doses. 

Patient enrolment/clinical trials/next translational steps:

For Spinal Cord Injury, this therapy is still at pre-clinical stage, with a clear objective to go to the clinics. Various studies and optimisation of the molecule need to be conducted before it is tested on human subjects with a spinal cord injury.