HSP clinical trial program update March 2020

Progress in preclinical studies

Frank McKeown



On the pathway towards a clinical trial, essential preclinical studies are in progress that aim to address two important questions:


  • What dose range of the candidate drug is to be used in a clinical trial?

  • How will the effectiveness of the drug treatment be measured and assessed in a clinical trial?

These simple questions unfortunately do not have simple answers.


Regarding dose range, preclinical studies need to establish evidence that meets both scientific and regulatory standards, resulting in researcher confidence and regulatory body approval to give particular drug doses to people in a clinical trial.


Measuring and assessing the effectiveness of a drug treatment requires the discovery and validation of a reliable biomarker* that is scientifically sound and, again, accepted and approved for use in a clinical trial by the regulator.

* A biomarker is a measurable indicator of the status (presence or absence; severity; stage of a disease) of something that can’t be measured directly. Biomarkers may be diagnostic (categorise disease) prognostic (assess risk of disease / progression) predictive (response to treatment) or pharmacodynamic (biological response to treatment). For example, body temperature is a biomarker for fever. Currently there is no measure of the status or rate of progression of most forms of HSP that is sensitive enough for measurements in clinical trials.


Alan Mackay-Sim

Dose range finding study (Brisbane, Australia)


Preliminary data from the second mouse study with a modified dosage range that began last November show that oral dose Noscapine is reaching the brain and spinal cord of mice. Also, levels of a compound that is a marker of microtubule stability are found to be elevated in the spinal cord of the mice in direct relationship to the different drug doses given.


Following the inconclusive results from the first dose range finding study in mice that was reported last June, the preliminary data available in this second study is promising and much more in line what was hoped for and expected.


The animal experiments and analysis of drug levels in the blood, brain and spinal cord of the mice were carried out at TetraQ  http://www.tetraq.com.au/, Research Infrastructure Centre at the University of Queensland. Analysis of the marker compound of microtubule stability in brain and spinal cord was done at the Queensland Institute of Medical Research (QIMR) https://www.qimrberghofer.edu.au/, also a facility of the University of Queensland.

Final reports from both organisations were not available at the time of this update but are expected in the near future. If the final reports support the indications of the preliminary data, the next step is to investigate what dose levels to test in humans, translating from the mouse study data. Members of the research team as well as appropriate experts in pharmacokinetics and pharmacodynamics will be working together to address this question.


Rebecca Schüle

Blood biomarker study (Tübingen, Germany)


Microtubules are talked about a lot in HSP research. That is because microtubules are a major building block of neurons. Neurofilaments are another main building block of neurons and, like microtubules, are rod-like protein structures that align in the long arm (the axon) of neurons (see diagram below).


They have been studied as a potential biomarker of disease status in neurodegenerative diseases such as motor neuron disease/ALS, Multiple Sclerosis, Alzheimer’s and Friedrich’s Ataxia.

Dr Rebecca Schüle and her team at the University of Tübingen in Germany set out to determine the value of two of the five different types of neurofilaments as potential biomarkers of SPG4 HSP in a study that began in 2018.

The project has been partially funded by this Foundation through community giving. The previous update on this preclinical study was published in June 2019.

The aim of the study is, in preparation for clinical trials, to determine if target compound levels measured in blood samples taken at several time points, increase or not over time and if that increase correlates or not with the clinical progression rate of HSP.

from ‘Intermediate Filaments as a Target of Signaling Mechanisms in Neurotoxicity’ by Ariane Zamoner and Regina Pessoa-Pureur


In this study, blood samples were taken and analysed from people with confirmed SPG4 type HSP from multiple locations including Germany, France and the USA. Sample collection from participants was completed in October 2019. Over the past six months, the data has been examined, analytical and statistical methodology chosen and applied, and results interpreted.

The main research questions to answer are whether or not:

  • target compound levels differ between HSP genotypes?

  • biomarker levels correlate with disease severity as measured by the Spastic Paraplegia Rating Scale?

Conclusions and recommendations are all that remain to be documented. The final report is currently in progress and expected to be completed by May, with findings hopefully able to be publicised soon after.


RA Ernadhi Liyanage, Dr. Gautam Wali, Dr. Sue-Faye Siow

Blood biomarker study (Sydney, Australia)


Two different types of samples from people with SPG4 type HSP and a matched ‘healthy control’ group are being investigated and compared in this study.


In the previous update, we reported that levels of the potential biomarker compound are significantly different in the HSP group compared to the non—HSP group. Previously, just one parameter of the biomarker was being investigated, but now, with more in-depth analysis, multiple parameters of the biomarker that can further distinguish HSP samples from non-HSP samples have been discovered.


Taking a multi-variate approach such as this will increase the potential of the biomarker to be successful as it will strengthen the validity, reliability, repeatability and effectiveness overall compared with reliance on a single variable.

The next step is to expand and repeat these experiments with a larger number of HSP participants. Plans for expanding involvement of the HSP community in the next phase of this work will be developed in the coming quarter. Work has also begun on a machine-learning approach to identify and predict disease status in individual cases of HSP.


  1. It looks like things are moving along very well. If you are working with the USA Boston I would love to help out I’m HSP SPG4.
    Thanks Nick

  2. Thank you for you efforts in helping us. I was diagnosed with SPG7. I’m praying for everyone for advances in this trial.

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