HSP Stem Cell research

Interview with lead researcher – June 2013


Prof. Alan Mackay-Sim
Prof. Alan Mackay-Sim

Interview with Prof. Alan Mackay-Sim, Co-Principal Investigator, HSP stem cell research.


Q: Very few cures for neurological diseases are available despite huge research investments in the past. Why is that and what is the current picture?
A: Neurological diseases are proving very difficult in finding drugs to treat them. The problem is such that many of the largest pharmaceutical companies are withdrawing from neurosciences research for commercial reasons. That means they have closed their own neurosciences research labs and just keep a watching brief on the field and make deals with academic researchers on an ad-hoc basis. The reason they are pulling out is because the old approach based on animal studies has not worked. Potential drug cures would look promising when tried on lab animals with neurological diseases, but then crashed out during clinical trials.


Q: What are the costs involved?

A: Traditionally it has cost hundreds of millions to go from a drug lead to an approved drug. $1 billion is often touted as the average cost. Clearly this is beyond everyone except large drug companies, and even beyond them when they have very few ‘wins’.


Q: So what does this mean for neurological conditions with small populations such as HSP?

A: Drug companies are generally not interested in rare diseases and small markets, but may be interested if someone else has taken all the risk and done all the work to prove that a drug works.


Q: How is this research trying to achieve that?

A: It is a new model, a new approach to neurological research. We are using stem cells developed from nasal tissue samples of people with HSP to study the disease, to work out what is happening in the diseased cells, to identify potential drug treatments and then to test them in depth for their ability to restore or compensate for impaired function caused by the HSP mutation. So all the way along we are using human tissue, and the hope is that this will be more informative and more relevant, and we do not have a lot of the unforeseen problems downstream that researchers have had previously translating results obtained using mice or fruit flies or other lab animals.


Q: What is the approach to finding a suitable drug?

A: We already know some of the specifications that a potential drug compound needs to exhibit, such as the ability to go from the blood into the brain so that it can do its work where it is needed. Beyond that, we are concentrating on identifying potential drug compounds that effectively treat the HSP stem cells, and the first place we are looking is to already accepted drugs – drugs for which there has already been human clinical use. If we find something there, then the cost of advancing to clinical trials and clinical usage is hugely reduced. Repositioning or repurposing of old drugs for new uses has been receiving a lot of investment and attention over the past few years. Between 2007–2009, 30% of all new medicines were either existing drugs or new formulations of old drugs.


Q: How do you go from a compound that is effective in the lab to a prescription drug available to people with HSP?

A: Firstly you look for a drug to positively affect a significant impaired function in the HSP stem cells. We achieve that by screening and we have identified some early-stage potential candidates. Next we try to understand how the drug works – what it actually does in the cell, whether it restores function or provides a workaround mechanism or affects something that affects something else. We need to know this to get approval from the regulator for a drug to be used, even if it is an already approved drug for something else. It also helps in the research needed to improve the drug for this new purpose. Then we validate the actions of the drug in a different biological model, for example in mice with HSP or in a different type of stem cell, called an induced pluripotent stem (iPS) cell. It may then be necessary to conduct a new Phase I safety trial, for example testing a drug previously used at high doses for short periods, for the new purpose at low doses for long periods. Then onto a Phase II efficacy trial that tests how well the drug works for the new purpose. With the repurposed drug, it may be possible to combine Phases I and II. Phase III follows, where the drug is tried on a lot of people in different locations. For rare diseases that qualify as ‘orphan’ diseases such as HSP, with a safe, repurposed drug it may be possible to get regulator approval without Phase III. Phase III is where the big costs come in.


Q: How long does all this take?

A: A long time. Scientists often say “5-10 years”. This is just to push expectations somewhere into the future. It depends on money and time given to the task as well as research success. But “10-20 years” is a better and more realistic estimate, and we are 5+ years down that path already, having initiated the HSP Stem Cell Pilot Study in 2008. Our approach is to try to shorten the time frame by first trying to find old drugs that might work with HSP. Because we are using stem cells from people with HSP, we can answer many questions about toxicity early on in the drug discovery process – and previous human usage helps answer these questions as well.


Q: What stage are we at right now?

A: We have moved into a new phase of work in 2013 titled Testing and Selecting Therapeutic Drug Candidates for treating HSP. We know what work is required here but there is no way to know how long it will take. We are at the drug discovery stage with some candidate compounds, confirming that they affect HSP stem cell functions and investigating how they do that. If these experiments are a dead-end, then it’s back to the drug-screening step. If successful, we move on to validate the next biological model e.g. iPS cells. That stage is likely to take at least a year, perhaps two, after which we hope to be in a position to move to early-stage clinical trials. This scenario all depends on the success of each step along the way. It will be longer if we have to go back to the drug-screening step. Drug discovery is after all “discovery” and there are risks of failure. Our job as scientists is to use our heads to predict the risks and know success when we see it. In the words of Louis Pasteur: Chance favours only the prepared mind. The speed of discovery depends on people, luck and money.


Q: Talk about the change of plans that you made in the last year?

A: We initially proposed to screen a library of around 900 known drugs. Our plans changed when we identified some known drugs that affected a relevant biological function in the HSP stem cells. Rather than continue with the drug screen, we chose to dig deeper on these potentially promising compounds. In many ways this took us past the screening phase and onto the next step. So with the knowledge gained we are now screening other known drugs that we predict will be useful, rather than the blind screening originally proposed.


Dr. Yongjun Fan
Dr. Yongjun Fan

Q: What is being worked on now and for the near future?

A: Fan is investigating the effectiveness of several drugs on cell function in the HSP stem cells. Gautam and Simon are studying disease-dependent cell functions in differentiated stem cells that are like neurons. This is the 1st stage validation.

All three researchers will then assess the effectiveness of selected drugs on cell function in the neuron-like stem cells. This is the 2nd stage of validation.

Simon Weyers
Simon Weyers

Simon is continuing to explore disease-dependent cell functions in HSP stem cells that are not Spastin mutations. The question being addressed is whether Spastin and and non-Spastin HSP cells have a common disease-causing pathway. As previously reported, there is some evidence already of a common pathway, leading to the possibility that treatments discovered for HSP caused by Spastin mutations might be applicable for non-Spastin HSP.

We are now planning to generate iPS cells from HSPers with Spastin mutations. Simon will be working on this with Prof. Carolyn Sue of the Kolling Institute of Medical Research who has worked collaboratively with us since the very start of the HSP research. The iPS cells are an independent model that can provide final validation of firstly the disease-dependent biological function, and secondly the effect of the selected drugs on this function.

Gautam Wali
Gautam Wali


iPS cells are more easily turned into cortical motor neurons and so will model HSP at a more specific level than the nasal stem cells we have been using to date. The nasal stem cells make a more practical early-stage model and iPS cells make a better validation tool.

The aim is to get this work completed in the 20 months left of the NHMRC grant that is providing the salaries for the 3 full-time dedicated researchers to the HSP program.


  1. I really enjoyed this article.
    Fingers crossed that the researchers are on the right track!

  2. We are fortunate that the HSP Research Foundation has been able to connect with such a dedicated team of researchers. Now there is hope for a treatment with medication in the future. Keep up the good work.

  3. Reading this article has given me hope. Thank you to everyone who is working so hard on this project. I not only have my fingers crossed, I’m also praying, they will have answers very soon.
    Thanks also to the volunteers within the HSP Foundation for making this possible.

  4. I am optimistic that the future will deliver a solution for HSP.
    My daughter is 23 and has always struggled to walk without pain and spasticity.
    I am praying that she can hold out before needing a baclofen pump

  5. why can’t we take from our children our relatives nasal stuff that does not have hsp? they do this for fecal transplant. they have some of the same genes.

  6. Editor’s Note: It has never been the intention of this research to use stem cells to treat HSP. The purpose of using stem cells derived from the nasal tissue of people with HSP is to study the disease. What you are referring to is called gene therapy, and there is nothing yet established in that field that indicates it as a potential treatment for HSP. This is different again from the purpose of faecal transplants, which is to introduce healthy microorganisms to fight nasty ones in the gastrointestinal system.

    The problem with HSP is impaired nerve signalling due to impaired cell function in the upper motor neurons, which are nerve cells in the brainstem. Any treatment needs to get to these nerve cells and reverse, compensate for, or restore normal functioning so that normal nerve signalling can take place from the brain to the (mainly lower) limbs. The best chance of that is in finding drugs that can cross the blood–brain barrier and have the required effects on those nerve cells.

  7. Does stem cell treatment work with HSP? if yes, where can i do it? If anyone knows, please answer me.

    1. Editor’s Note: There is a significant amount of discussion of the potential for gene editing therapy involving stem cells to cure genetic diseases, however there are many unanswered fundamental questions at this stage, and any prospect for this type of cure is realistically many, many years away.

  8. I have heard many good things about stem cells. How can we get info on this? Where can we go to try this? Is there any clinical trials?

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