Background information:

Funds from endParalysis enabled a pilot collaboration between Dr Murray Blackmore of Marquette University and Dr Steve Perlmutter of Washington University to test a novel 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 was based on a recent discovery by Dr Blackmore’s lab that a combination of two transcription factors, Klf6 and Nr5a2 (KN), stimulates robust and highly reliable growth of Corticospinal tract (CST) axons. The goal here was to translate by determining whether KN is also effective in a more chronic and clinically relevant model of spinal contusion in Steve Perlmutter’s laboratory at the University of Washington. Read this blog post for more information about the project and its selection.

Latest update (May 2022):

The treatment showed promise in animal experiments when applied acutely to a mild injury, raising the question of whether it could be as effective in more severe and chronic injuries. With support from endParalysis, Blackmore and Perlmutter conducted a series of experiments to establish viral designs and surgical techniques for administering the treatment to rats in the chronic stage of spinal cord injury. Using this pilot data, the two laboratories were able to obtain additional funding from the Craig H. Nielsen foundation to comprehensively test this approach for improving recovery and functional recovery after chronic spinal cord injuries.

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

Patient enrollment/ clinical trials/ next translational steps:

This therapy is still at the preclinical stage. Several studies need to be conducted before it is tested on human subjects with spinal cord injury.

Background information:

Overexpression of FL2 (an inhibitory protein) after spinal cord injury results in inhibition of axon growth. Preclinical research suggests that siFi2 (a drug developed by US biotech company MicroCures) can suppress the activity of FL2 and thus trigger the regeneration and reattachment of axons at the site of injury. This therapy is based on switching off proteins and enhances the body’s intrinsic healing processes.

Latest update (Oct 2023):

Following the promising functional improvement observed in previous acute studies, endParalysis and partners MicroCures and USU (Uniformed Services University of the health science – Maryland, USA) have asked to test the siFi2 therapy in rats with chronic injuries (endParalysis co-funded this project through a research grant in 2021). The results of the study, as shared in October 2023, are encouraging. The experiment showed that the treatment is also effective at a later stage of injury, with improvements in both the BBB score (gait and step test for rodents) and gait pattern of the treated animals, compared with the control group.

Patient enrolment/clinical trials/next translational steps:

This study is still in the preclinical phase (animal trials). However, we consider it to be a promising therapy. The therapy will need to be further replicated in another laboratory and tested on a larger number of animals to demonstrate robust effects and possible translation to the clinic.

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.   Gusu2cure (USA) and the Marina Romoli Onlus (Italy). 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. 

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 non-invasive character of the CRP (it can be applied by subcutaneous injection) is of great interest. CRP treatment, if proven effective, would 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. The endParalysis foundation and partners supported various animal studies to check the robustness, replicability and safety of the CRP therapy in order to advance it towards human trials

Latest update (October 2023):

• 2022-2023 CRP replication + combination study (Ronaldo Ichiyama’s lab, Leeds, UK): This animal study was co-funded by endParalysis and partners in 2022. The experiment was meant to check whether the behavioural improvements seen by the animals treated with CRP could be replicated by another lab, and whether they could be enhanced by the electric stimulation of the cord. E-stim through an implanted stimulator has repeatedly been shown to (slightly or significantly) improve behavioural outcomes in a number of human subjects by “awakening” the spinal cord neural connections that had become “dormant” as a consequence of the injury.
  Unfortunately, the effect of the CRP peptide was not proven by this study: there was no significant difference between groups treated with e-stim only and the groups treated with E-stim+CRP.

• 2020-2022 CRP dosing study (Yu Shang Lee’s lab, Cleveland Clinic, USA): funds were pre-allocated by endParalysis and partners at the end of 2019 for testing dose responses of CRP. The goal was to confirm previous outcome and to see if a higher CRP dose could lead to additional functional improvement, after chronic spinal cord injury. Dr Yu Shang Lee reports “We have demonstrated the efficacy of CRP treatment to repair chronic SCI by improving locomotion (in the first progress report) and lower urinary tract function. In anatomical study, we also showed the CRP treatment can reduce glial scars and enhance the sprouting of serotonergic fibers that may leading to the functional recovery”.

• 2018-2019 rodent study (Yu Shang Lee’s lab, Cleveland Clinic, USA): 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 endParalysis in 2018, 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 by Dr. Jerry Silver’s lab to have a robust effect at the ACUTE stage).

   

Patient enrolment/clinical trials/ next translational steps:

Over the period 2020-2023, endParalysis’ partner (Niall’s foundation - UK) funded independent CRO (Contract Research Organization) testing of CRP including pharmacodynamics (PD: studying the action of the drug on the organism) and pharmacokinetics (PK: studying the effect the organism has on the drug). These tests are necessary for any therapy advancing to human trials. The various in vivo and in vitro experiments carried out by the CRO have unfortunately failed to show a robust reach and effect of CRP when delivered subcutaneously.

However, a study carried out by  Dr. Brian Kwon (Canada) and funded by the DoD (Department Of Defense, USA) is currently testing the CRP in a larger animal model (mini-pigs with a T10 subacute spinal cord injury), using an intrathecal administration. We are looking forward to the results of the latter study. 

Background info:

The application of a bacterial enzyme (a protein) called Chondroitinase, or Ch’ase, has repeatedly been proven to degrade the scar, to promote growth and to improve recovery in animal experiments. However, applying it to people is challenging. The goal of the project “CHASE-IT”, initiated by the International Spinal Research Trust (ISRT), is to make the Ch’ase therapy ready and safe for clinical application. It relies on an international collaboration between various researchers, among others in the UK and in The Netherlands. Recent experiments, using gene therapy models to deliver the enzyme, have moved the therapy closer to human application. The gene for Ch’ase is expressed in an active form in human cells and can be switched on and off to ensure an optimal and controlled delivery.

Latest update (Oct. 2021):

Two alternative gene delivery therapies have been developed/ are being tested  :

Patient enrolment/clinical trials/ next translational steps:

-The AAV vector, once optimized, will be tested in both acute and chronic SCI models (rodents).

- Discussions are ongoing to test the best version of the chondroitinase therapy on humans. This is, however, a long-term goal. Meanwhile, additional animal studies are being conducted and are funded by Wings For Life. For the latest update on this line of research, see our Research Overview page, here.