This is the second of three notes I’ll write documenting what was presented at fara‘s Patient Information Forum in November 2020. It was an information-packed event and I’m delighted I saw it live. Even if you didn’t though, the presentations were all recorded and you can still view them. I’m not a researcher or a scientist. This note tells what I, a simple FAer, understood from the presentations. So, as I said before, I still recommend very strongly that you make time to see and hear the full presentations from the researchers themselves.

To view them, click here and when it asks for a passcode, enter: Bbv2Nl=P (that’s a small letter L after the N). It might appear that only the first 45 minutes is recorded, but when that is finished playing, the recording of the rest appears, as if by magic.

After Sherelle, Jen and Kara that I spoke of in my last note came Martin Delatycki who explained the work his group coordinates via the Murdoch Children’s Research Institute in Melbourne.

Some of those are addressed elsewhere in these notes. A few that aren’t are:

• Instrumented measures of Ataxia: Louise Corben and colleagues from the Howard Florey Institute at Deakin University are working to develop a cup and a spoon with sensors attached that allow their movement to be tracked in 3D. This will enable smoothness and accuracy of movement using everyday objects to be measured so they can be used to evaluate severity and progress of ataxia and potentially as objective evaluation criteria in clinical trials. Having recognised outcome measures like this can be critical to getting FDA (and other regulatory agency) approval for new drugs.

• Trials: I covered Kara Fick’s presentation about the status of the MOXIe trial (also known as Omav) in my earlier note. The Resveratrol and PTC-743 trials are recruiting now including here in Australia. For more information on them, please make contact with Louise (louise.corben@mcri.edu.au).

• Clinical Management Guidelines: It’s been spoken of many times that while all physicians in Australia learn about FA in their training, with fewer than 400 actual FAers in this country, precious few ever encounter it in the course of their practice. FARA ran a project some years ago to collect key learnings and best clinical practice for FA care across a wide range of disciplines. This was an enormous project, led by Louise and her colleagues in Melbourne and valid throughout the world. It was first published in 2014 and is in the process of being updated. (It’s so comprehensive a separate “User’s guide” was published alongside it).

  • NB While the goal is for the update to be published by mid 2021 we’re all familiar with how world events can derail timings of things. Every FAer should download and be using the current issue in the meantime. Click here to download a copy which you can give to any healthcare professional you work with. (If you contact me (terry@fan.asn.au), I have a few of the USB bracelets too).

  • Edit (2024): The updated version is WAY too big to download. Go on, click here and have a look. Simply share this link with your GP and with all your therapists: frdaguidelines.org.

• Gene therapy preparedness: I wrote briefly in my previous note about gene therapy. It sounds relatively straightforward in principle but is way more complicated in practice. The theory is to introduce a vehicle to carry an edit that’ll correct the GAA expansion on an FAer’s FXN gene. Some complications are:

  • The “vehicle” has to find the FXN gene which is on a DNA strand that probably contains more than 20,000 individual genes. That requires advanced genetics.

  • This “editing” will be a chemical process that’ll happen at a micro- micro- microscopic level. That requires advanced chemistry.

  • The “vehicle” needs to do its editing job, then go on to do it again and again. So far the best such “vehicle” found like that is a non-harmful virus. That requires advanced virology.

  • Only a handful of gene therapy trials have ever been run in Australia and none has in Melbourne before. Professor Delatycki’s team are working on a number of things simultaneously to get ready to be able to conduct a gene therapy trial, but also to establish a set of protocols that can be followed in subsequent legs or even separate trials elsewhere. That involves:

    • Procedural & facilities protocols (such as the specific location where the trial can occur)

    • Ethics & regulatory preparation & submissions

    • Regulatory presentations & submissions

    • The relevant institutions need to be prepared, such as pharmacy & laboratory staff

    • Participant preparation including a current qualitative research study (interview FAers to determine how much do we understand), development of educational presentations (what we need to understand) and explanatory/informed consent forms (that we’ll need to sign before participating to confirm we understand).

“Whoa!” says Mirella Dottori, “The theories are fantastic, getting to human trials will be even better. But there are critical steps in between. Let me tell you how we’re addressing them.”

Have you heard of “in vitro” and “in vivo”? Well they refer to development using cells in the lab (in vitro) and animal or human trials (in vivo). It’s possible, therefore it’s essential, to prove that a treatment works on cells in a lab before trying to prove that it’ll work in a live subject.

Mirella’s team make that more worthwhile though. They don’t just work with any cells, but iPS cells. Think of it this way: an adult human body has about 30,000,000,000,000 cells and they’re pretty specialised – skin cells, bone, heart etc. Cells divide and reproduce, but once they’re specialised, so will be their next generation. FA impacts different cells in a different way and to a greater or lesser degree so it might be pointless developing a treatment if it would be applicable only to a particular kind of cell. But we all started out as a single cell – a fertilised human egg. It wasn’t specialised at that stage, it was pluripotent – it had the potential when it divided and reproduced, to become any kind of cell. Mirella’s team works with chemistry that lets them take an FAer’s skin cells and transform them back into pluripotent stem cells; then use them to trial stuff on in the lab.

The advantages are enormous. Because a treatment would be applied before the cell becomes specialised, it would carry that benefit (for example, the ability to make Frataxin more efficiently) as it becomes specialised.

Just as they’ve developed chemistry and technologies to reverse cells back to pluripotency, so they’re identifying ways to nudge iPS cells to become specialised again as cells of the type most affected by FA. A key way treatment may develop for FA might not be a pill or gene therapy. It might involve stem cell treatment individualised to each FAer.

Don’t believe everything you read or hear about stem cell therapies. What’s available today is rubbish at best, dangerous at worst. When a stem cell treatment relevant to FA is proven, Mirella will tell us about it (and may have had a role in developing it).

D’you remember some years back there were worrying stories about sun cream containing nanoparticles? Particles so small that they might be able to get anywhere inside our bodies and wreak havoc when there? Well, those fears didn’t come to much and Christina Cortez-Jugo, who works in collaboration with Mirella, tells us that even nanoparticles haven’t got the ability to go wherever they like. Even at that tiny scale, it can be a hostile environment and the wrong kinds of particles don’t last long.

Christina leads a group of engineers at the University of Melbourne who build (yes seriously, they build) different kinds of nanoparticles (nano, meaning really very small indeed! Imagine you were a period, a full stop. How big would a tennis ball seem to you? Now, how small would something be for it to think of you as tennis ball big? And scale down one more time again. Yes, that small). Christina’s group build nanoparticles that a section of DNA containing instructions to make Frataxin can be put inside, and they can carry it into the nucleus of cells. They tried it out with DNA-sized instructions for a cell to make itself fluorescent, and because of the fluorescence, can see that the cell can produce fluorescent protein inside the cells. Next, they will test if it will work with Frataxin-making instructions, and how to ensure they do their job inside the right cells. Progress is infinitesimally small, but at the scale Christina works, that’s equivalent to making big strides forward

That’ll wrap up the second of my notes on the info webinar. There’s still one to come. Cheers.