Research program update March 2021

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The Research Program update on the clinical trial for March 2021 can be viewed as a video. Read the full report below for more about other parts of the research program.

Drug supply for the trial

The drug supply process is stalled despite our best efforts to secure the specified drug treatments for the proposed Phase 1 & 2a trials. As reported in the last update, this can’t be done in Australia, with the international supply chain continuing to be disrupted by the global pandemic. There have been recent reports of supply problems and shortages in Australia of certain prescription medications, apparently for the same reasons.

Plan for Phase 1 alone

Given this reality, the decision has been taken to separate the Phase 1 trial from the Phase 2a trial rather than proceed with them as a package as has been planned for to date. The thinking is that this will give us a better chance of getting the clinical trials started and moving and get some results on the highly important Phase 1 study of human safety and drug tolerability at the prescribed doses for testing.

The design for the Phase 1 study will be enhanced somewhat, with additional measurements of the pharmacokinetics (PK)* and pharmacodynamics (PD)* at play, that is, how much of the oral dose of the drug is in the blood at various doses and times after taking the medication; and what effect is the drug having on the HSP biomarker. This data will feed into Dr Wali’s study of the biomarker and the process of biomarker validation (see separate report below on progress with biomarker development).

These findings will be somewhat of a bonus on top of the central focus of Phase 1 studies, namely the health and safety of participants, which is based on multiple measures and diligent scrutiny for any drug side-effects or adverse reactions in trial participants.

*Learn more about PK & PD

Dr Gautam Wali

HSP biomarker** development (Sydney)

Blood biomarker

The work on developing a high-throughput assay for the HSP biomarker that is sensitive to drug treatment levels in blood samples and suitable for use in clinical trials has advanced over the quarter. As part of as a development, samples of brain tissue from the mice used in last year’s drug dose range-finding studies in Brisbane are being evaluated. This is the first time that brain tissue samples are being used for this purpose, with the need for optimisation of the higher protein concentration found in brain tissue compared with blood. With a large range of protein concentrations needing to be tested across multiple samples, this was a time-consuming step that has now been successfully completed. The next step is to test all the mice samples.

Skin fibroblast biomarker

Work continues on analysis of experimental data to develop this biomarker for HSP diagnosis and drug testing. This is the first time that an approach combining machine learning and high-content microscopy image analysis to compare and distinguish between HSP and healthy skin cell samples has been applied to any neurodegenerative disease. This ‘Cell Morphomics’ approach can be thought of as measuring and comparing critical differences in cell morphology between diseased and healthy cells – differences in size, shape and structure in a precise and reliable way.

** 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.


During the quarter, the Foundation approved funding for the HSP biomarker high-throughput assay development project in the amount of $69,000.


    1. Editor’s Note: Have a look at the information on this website under the ‘About HSP’ tab This looks at genetic and cellular components of how HSP happens, and also talks about treatment of symptoms. Right now, there are no ‘disease-modifying’ treatments or cures for the HSPs, although that day is getting closer as both drug and gene therapy treatments have been identified and are in the process of being evaluated, such as the SPG4 clinical trial program supported by this Foundation.

      1. 1. Assume that HSP is caused by contamination of food and water
        2. HSP is transmitted through the blood to healthy people
        Is either of these possible?

        1. Editor’s Note: All 90 or so forms of HSP found so far are genetic diseases associated with mutations in about 70 genes. Almost all HSP is passed on from parents to children, with a small percentage the result of genetic ‘mistakes’ that just happen as with all natural biological processes.
          Regarding point number 1 in your question – if you are asking ‘what caused the mutation in the first place?’, the explanation with by far the most supporting evidence is that when fertilisation occurs with egg and sperm fusing to produce a new organism, there are tens of thousands of genes being passed on in a process of selection for each gene, which comes from either the egg or the sperm. If either the egg or the sperm, or both, carry mutations associated with HSP, there is the chance of them being passed on. In some cases, with this being a biological process that is not perfect, mistakes happen with the result that genetic mutations occur out of nowhere – genetic code gets scrambled. Whether or not these gene variants are passed on or just happen randomly (sporadically), everyone has them. Sometimes these genetic variants are associated with disease. Whether or not there are environmental factors such as contamination of food and water that cause HSP by changing our DNA (mutagenicity) or damaging our DNA (genotoxicity) in the first place is unknown, however at this point there is no evidence for this. The field of epigenetics studies the impact of environmental factors on genetics, so definitive answers to this question may emerge as the science develops.

          Regarding point number 2: the answer is ‘No’.

  1. In the mouse trials, did Noscapine improve current gait problems, or just stop further disease progression?

    1. Editor’s Note: The pharmacokinetic and pharmacodynamic studies were done with healthy mice, looking at drug and biomarker levels in blood and nerve tissue. These were dose range-finding studies to indicate appropriate dosing regime in clinical trials. They were not aimed at testing the effectiveness of the drug. Only very recently have HSP mice with mobility impairment been successfully bred. This is in the Baas lab at Drexel University, Pennsylvania.

    1. Editor’s Note: No, the phase 1 study has not yet commenced. Quotes have been obtained and discussions with contract research organisations and service providers such as clinical trial monitors and statisticians have been had.

  2. Are researchers using a special type of Noscapine in clinical trials? Research shows, “There have been multiple tests demonstrating noscapine’s low toxicity to organs and tissues. With very high doses, the side effects have only consisted of nausea and abdominal discomfort in a small percentage of patients” (Padmashree, LiVecche, Ogden, Zhou, and Aneja, 2015). What are safety trials researching specifically? It seems like HSP clinical trials would not need this safety phase and could skip to human trials focusing on drug effectiveness since Noscapine has been used for over 40 years in humans.

    Padmashree C. G. R., LiVecche D. , Ogden A. ,Zhou J., Aneja2 R., 2015. The Noscapine Chronicle: A Pharmaco-Historic Biography of the Opiate Alkaloid Family and its Clinical Applications. Pubmed doi: 10.1002/med.21357

    1. Editor’s Note: No, no special form of the drug. The active ingredient is the same as has been used for over 40 years, as you point out. The research team was hopeful of avoiding the need for a phase 1 clinical trial of safety and tolerability, however the dose range-finding studies showed activity in the levels of the biomarker for microtubule dynamics in a range not approved for human usage. Together with the results of other safety studies, this meant that undertaking a phase I trial became necessary.

  3. In nipa1 hsp, how important is bmpr 2 activation?
    Can bmpr 2 activation with fk506 tacrolimus restore spg6 or nipa1 hsp?
    Or can inhibiting bmpr2 restore spg6 function?
    Please help editor

    1. Editor’s Note: If there is anyone who can answer your questions, it will be researchers who are working in this area and have published on it. Recommend you contact the authors of relevant publications. Neither these forms of HSP normal BMP processes are being studied by our research team. Perhaps Dr Evan Reid at Cambridge University may be worth trying?

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