Promising results in HSP drug candidate class

Posted - September 2015 in Research Highlights

Nerve axon regeneration and improved motor function

 

The cancer drug epothilone B reduced the formation of scar tissue in injuries to the spinal cord and stimulated growth in damaged nerve cells in rats. Both effects promoted neuronal regeneration and improved the animals’ motor skills.

 

Prof. Alan Mackay-Sim

Prof. Alan Mackay-Sim

Prof. Alan Mackay-Sim commented “It is not out of the range of possibilities that epothilone B might be effective in people with HSP if it were able to rescue the death of corticospinal axons and assist their regeneration.”

 

Epothilone D, an almost identical compound to epothilone B, is a leading drug candidate emerging from the HSP research at Griffith University that is supported by this Foundation. In that research, epothilone D was found to reverse the impairment and restore function in HSP stem cells. Principal Investigator, Prof Alan Mackay-Sim made the following comments on this new study:

This recent paper in the eminent journal Science follows on from a body of work suggesting that drugs that stabilise the microtubules, part of the cell “skeleton”, can assist in repair of the nerve cells after spinal cord injury. Spinal cord injury cuts the axons of neurons. Axons are the long processes that connect neurons together. Spinal cord injury cuts these axons and causes them to retract, leading eventually to neuron death. Tubulin stablising drugs are used at high doses in cancer to stop cancer cells proliferating but at very low doses they can be beneficial by promoting axon recover and regrowth after spinal cord injury.

Nerve Cell (Neuron)

Nerve Cell (Neuron)

This study shows that epothilone B leads to regrowth of damaged axons and leads to recovery of motor functions after spinal cord injury in the rat. This work is exciting because epothilone B is already used clinically in humans, it can be injected and it can reach inside the brain and spinal cord, and it is used at very low doses. It is therefore a potentially injectable drug to assist recovery after spinal cord injury in humans. It is not out of the range of possibilities that epothilone B might be effective in people with HSP if it were able to rescue the death of corticospinal axons and assist their regeneration.

 

Abstract

After central nervous system (CNS) injury, inhibitory factors in the lesion scar and poor axon growth potential prevent axon regeneration. Microtubule stabilization reduces scarring and promotes axon growth. However, the cellular mechanisms of this dual effect remain unclear. Here, delayed systemic administration of a blood-brain barrier-permeable microtubule-stabilizing drug, epothilone B (epoB), decreased scarring after rodent spinal cord injury (SCI) by abrogating polarization and directed migration of scar-forming fibroblasts.

Conversely, epothilone B reactivated neuronal polarization by inducing concerted microtubule polymerization into the axon tip, which propelled axon growth through an inhibitory environment. Together, these drug-elicited effects promoted axon regeneration and improved motor function after SCI. With recent clinical approval, epothilones hold promise for clinical use after CNS injury.

 

SOURCE: Science. 2015 Apr 17;348(6232):347-52. doi: 10.1126/science.aaa2958. Epub 2015 Mar 12. Copyright © 2015, American Association for the Advancement of Science. PMID: 25765066 [PubMed – indexed for MEDLINE] PMCID: PMC4445125 [Available on 2016-04-17]

 

Axonal regeneration. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury.

 

Ruschel J1, Hellal F1, Flynn KC1, Dupraz S1, Elliott DA1, Tedeschi A1, Bates M2, Sliwinski C3, Brook G4, Dobrindt K5, Peitz M5, Brüstle O5, Norenberg MD6,Blesch A3, Weidner N3, Bunge MB2, Bixby JL2, Bradke F7.

  • 1Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
  • 2The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 Northwest 14th Terrace, Miami, FL33136, USA.
  • 3Spinal Cord Injury Center, Heidelberg University Hospital, Schlierbacher Landstr. 200A, 69118 Heidelberg, Germany.
  • 4Institute for Neuropathology, RWTH Aachen University, Steinbergweg 20, 52074, Aachen, Germany. Jülich-Aachen Research Alliance-Translational Brain Medicine.
  • 5Institute of Reconstructive Neurobiology, Life&Brain Center, University of Bonn and Hertie Foundation, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
  • 6Departments of Pathology, Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, FL 33101, USA.
  • 7Axonal Growth and Regeneration, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. [email protected]

 

Comments on this story

  1. Grant posted at 1:31 pm on 3 September 2015Reply

    This sounds great, what is the next thing that we can do to try or what ever.

    • Editor posted at 3:27 pm on 3 September 2015Reply

      Hi Grant,

      There is nothing out of this that can be done. The significance of the results of this study are that they are indirectly supportive of the work and direction being undertaken by the HSP research team funded by HSP community members through the Foundation. Why I say ‘indirectly’ supportive is that the drug used in the study, whilst almost identical, is not exactly the same one being tested by the HSP team; secondly, the study was of spinal cord injury when nerve axons are physically severed… this is different to HSP where there is slow degeneration of the axons.

  2. fender posted at 5:22 pm on 3 November 2015Reply

    has it been tested by someone with hsp

  3. Yanqi posted at 3:52 pm on 28 December 2015Reply

    Dear Professor Alan Mackay-Sim,
    Do you know if Epothilone B or similar chemical(s) has been used in healing human spinal cord injury? My brother got his spinal cord injured badly in a car accident. I would appreciate information that you can provide.

    Thank you, Yanqi

    • Editor posted at 3:58 pm on 29 December 2015Reply

      Editor’s Note: Prof Mackay-Sim replies to your inquiry as follows: “There is no clinical use of Epothilone B in humans as far as I am aware.”

      Yanqi, Prof Mackay-Sim has however been involved in the use of nasal stem cells for the first-ever successful repair of a severed spinal cord allowing the patient to walk again http://www.hspersunite.org.au/alan-mackay-sim-receives-worldwide-recognition/. Read that article and click the link to take you to the story in the Australian newspaper. This is a potentially more promising path for your brother.

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