Onderzoek strategie & financiering

Onze onderzoek-strategie

Onze selectie- procedure

Gefinancierd onderzoek

  Dwarslaesie zal genezen worden…

…maar zover zijn we nog niet. We gebruiken alle fondsen die we ontvangen doelgericht om onderzoek te versnellen, zodat mensen die nu met een dwarslaesie leven een kans krijgen tot herstel

Hoe garanderen wij wetenschappelijke nauwkeurigheid?

Ons professioneel selectieproces hieronder zorgt ervoor dat de projecten die we financieren in lijn zijn met onze strategie en wetenschappelijk rigoureus zijn

Waar gaat uw geld naartoe?

100% van uw gift gaat naar onderzoek om chronische dwarslaesie te genezen. Hieronder kunt u de details zien van onze projecten.

Onze onderzoek- strategie 

Wat wij doen, onze focus

 

We hebben momenteel drie actiepijlers:

  • Beïnvloeden van Onderzoek, Informeren -> We werken actief samen met de wetenschappelijke gemeenschap om meer doelgericht onderzoek te bevorderen & dwarslaesie-patiënten/families te informeren over het nieuwste onderzoek naar herstel
  • Gericht onderzoek financieren -> We financieren onderzoek dat welomschreven uitdagingen of obstakels voor de vertaling van behandelingen aanpakt en alleen als het kan worden toegepast op mensen die momenteel leven met verlamming (“chronische” dwarslaesie)
  • Versnellen van menselijke vertaling -> We nemen stappen om ten minste één veelbelovende therapie versneld van het lab naar de kliniek te brengen. We doen dit via partners die hetzelfde doel hebben als endParalysis – curatieve behandelingen zo snel mogelijk bij patiënten krijgen.

Onze onderzoek- richtingen

Onderzoek naar biologisch, functioneel & sensorisch herstel voor herstel na chronische dwarslaesie, incl.:

  • Littekenreductie -> Verwijderen van het litteken (dat in het chronische stadium van het letsel blijft bestaan en de hergroei van zenuwen verhindert). Dit heeft ook tot doel de neurale plasticiteit te vergroten, zodat nieuwe verbindingen kunnen worden gemaakt en het lichaam opnieuw kan leren. 
  • Hergroei van zenuwen regrowth-> Axonen (zenuwen in het ruggenmerg) opnieuw laten groeien over de laesie heen om nieuwe verbindingen te maken en de communicatie tussen de hersenen en andere delen van het lichaam te herstellen en natuurlijke, biologische functies en sensaties mogelijk te maken. 
  • WeefselvervangingVervangen of herstellen van motorneuronen of andere onderdelen die beschadigd zijn en nodig kunnen zijn om de verlamming volledig terug te draaien.

     

Hoe we dwarslaesie-onderzoek- projecten selecteren voor financiering

Stap 1: preselectie

 

Een projectvoorstel wordt voorgeselecteerd door het bestuur van EndParalysis (EP) als:

  • Het project voldoet aan de drie selectiecriteria van de stichting (1. Toepasbaar op chronische dwarslaesie, 2. Voornamelijk biologisch,  3. Potentie biedend om naar de kliniek te gaan).
  • De voorgestelde therapie lijkt aan te sluiten bij de belangrijkste onderzoeksrichtingen van endParalysis en de gerichte portefeuille van behandelingen
Stap 2: wetenschappelijke beoordeling

 

Het voorstel wordt zorgvuldig bekeken en beoordeeld door wetenschappers::

  • Ofwel de wetenschappelijke adviescommissie van endParalysis, ofwel
  • Het wetenschappelijk adviescomité van een partnerorganisatie (om belangenconflicten te vermijden), of
  • Een aantal geselecteerde deskundige wetenschappers (om een zeer specifieke expertise te garanderen die nodig is voor een bepaald project)
Stap 3: finale validering

 

De definitieve validatie vindt plaats volgens onderstaande stappen:

  • Het EP-bestuur stelt de wetenschappelijke beoordelingen samen
  • Zij bespreekt de vragen van de beoordelaars met het lab van de onderzoeker
  • Zodra alle belangrijke opmerkingen kunnen worden weggenomen door verduidelijking, en ALS de meerderheid van de definitieve wetenschappelijke beoordelingen wel financiering aanbeveelt, valideert de EP-raad het voorstel.

 De dwarslaesie onderzoek -projecten die we tot nu toe hebben gesteund

-Introductie Update juni 2022 – Deze rubriek is in opbouw en zal binnenkort worden bijgewerkt

Lopende financiering (2018-2021)

CRP (CSPG Reduction Peptide) – to reduce the scar at CHRONIC stage – Dr. Yu Shang Lee – Pre-clinical stage (Animal studies - USA)

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 (Oct. 2021):

– 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”.

     

    – 2020-2021 dosing (rodent) study:  the CRP dosing study (funds pre-allocated by endParalysis at the end of 2019) is  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 suffered some delay due to the COVID-19 lockdown measures. However, the preliminary progress report relates very encouraging results. We expect the final report to be available by the end of 2021 and will share the conclusion on our website.

    Patient enrolment/clinical trials/ next translational steps:

    – We hope to receive the final results of the 2020 CRP dosing animal study funded by endParalysis by the end of February 2022

    – 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 and results are expected in 2022.

    – 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.

     

    Microcure and University Pre-clinical stage (animal studies- USA)

    Background info:

     

    Latest update (Nov. 2021):

    Patient enrolment/clinical trials/next translational steps:

     

    KN combined gene therapy- Blackmore Lab – Pre-clinical stage (animal studies- USA)

    Background info:

    Funds from endParalysis enabled a pilot collaboration between Dr. Murray Blackmore and 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. 

     

    PNN-i study- Dr Kwok- University of Leeds- UK (animal study for SCI, but this drug is already on the market for other conditions)

    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 (Nov. 2021):

    PNNi dosing study (including chronic SCI) by the Kwok Lab: this study was co-funded by the endParalysis foundation at the end of  2020 together with two other foundations: We thank the Marina Romoli Onlus (Italy) and  Gusu2cure (USA) for accepting to fund this project with us.  The animal study is ongoing. It is aimed to check if the PNNi molecule (an oral drug) works as well in chronic settings as in acute settings, and whether a higher dose is needed for chronic spinal cord injury. Also it will be scientifically checked what lowest possible quantity enables to keep the therapeutic effects intact while avoiding unfavourable side-effects. The first report regarding this study is positive, but the final report will only be received in 2022.

    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 need to be conducted before it is tested on human subjects with a spinal cord injury. 

     

    Periode daarvoor  (2015-2017)

    CH’ASE IT: Chondroitinase and gene therapy for chronic SCI- PRE-CLINICAL stage (ANIMAL STUDIES - UK- NL)

    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  :

    a- The chondroitinase enzyme is delivered via a Lenti-virus vector (a virus made harmless and capable of carrying therapeutic genes). The consortium demonstrated this exciting new approach gave rise to improved walking and unprecedented upper limb function in rodent acute spinal cord injury models. See more information in this article and video and this Brain publication (August 2018). The same treatment was tested in a rodent chronic injury model at the end of 2018. The latest chronic trial has only shown modest results in terms of recovery and the current focus of the researchers is to combine treatment with rehabilitation to improve. More work has yet to be carried out to obtain the expected functional efficacy.

    b- The Ch’ase enzyme is delivered via an Adeno-associated viral (AAV) vector which has the advantage of already being used in other human treatments and would, therefore, allow easier access to clinical trials. Various AAV vectors were created by Verhaagen’s lab and tested but they need further adjustment to ensure that the vector can be totally switched off when needed, without any further leakage. Indeed, one issue researchers found with AAV vectors was a noticeable background expression of the chondroitinase in the “off” setting.

    The first two rounds of studies were co-funded by the endParalysis foundation and Spinal Research in the UK up to 2019. The follow-up studies are funded by the Wings for Life foundation as of 2020. The current study specifically focuses upon applying Ch’ase on rodents with a chronic SCI and combining with physio therapy to improve functional results.

     

    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. 

    Neem contact met ons op

    info@endParalysis.org
    Stichting endParalysis

    Cederlaan 135
    5616 SC EINDHOVEN
    THE NETHERLANDS

    (+31) 6 22 788 798
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    @endParalysis
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