DNA-based gene therapies have the potential to revolutionize our understanding of rare diseases and offer new treatments.

To learn more, I talked to University of Toronto researcher Rachel Harding about medical breakthroughs in Huntington's disease.

Then I spoke with Terry Pirovolakis about his young son, Michael, one of an estimated 80 children around the world with a condition known as spastic paraplegia type 50.

Terry shares the story of how Michael's life was changed thanks to the first single-patient gene therapy trial at SickKids Hospital in Toronto.

Rachel, Terry, welcome to The Rundown. How are you doing?

Great. Thank you for having us.

Yeah. Thank you for having us. This is awesome.

Yeah. No worries. Rachel, let's start with you. Walk us through the recent Huntington's disease gene therapy. Specifically, what does 75% slower disease progression actually mean?

Yeah. So maybe let's start with what Huntington's disease is. So this is a rare inherited neurodegenerative disease characterised by progressive which means symptoms that get worse and worse over time, which are motor movement thinking and psychiatric symptoms as well.

And everyone who has Huntington's disease makes a slightly different version of a protein called the huntingtin protein.

And so the gene therapy that was designed by this company, Unicure, is delivered by brain surgery.

And it's a genetic instructions that are packaged into this harmless virus that spreads through the brain and tells the brain to make less of this kind of harmful form of the huntingtin protein.

And so there's been a whole bunch of folks who've been in this clinical trial for quite a long time now, and we just got some data a few months ago now, which seems to suggest that there was slowing of symptom progression by about 75%.

And so this is equated to symptoms that would normally progress in their aggressiveness in the course of a year. That would now take four years.

Okay. So this is really exciting. This is the first time any company has shared a, any data that seems to suggest that they're able to slow down the course of the disease.

We do have to be a little bit careful, though, because this is a very small trial.

How many people? 12 people. Okay.

So which is because we don't want to give brain surgery gene therapies to hundreds of people at once until we're really sure, you know, are they safe? How well might they be working? We need to get some good signals from those first.

And so we've just got 12 people.

And the other problem with these trials is it's not always practical or ethical to do a placebo arm.

So actually what they're doing is they're looking at what they call a natural history cohort.

This is where they track data from people who have Huntington's disease, but they're not in the trial.

And we're trying to see how they would progress without the drug and then making that comparison.

And so there's a bit of a debate about how good that is as a comparator.

But nonetheless, it's still an encouraging step forward.

And I always like to think about these super brave people who took this gene therapy, had this brain surgery before they knew there was any possibility this might be definitely okay.

And they've been walking around for the last few years with this gene therapy and their brain lowering the amount of this toxic protein and how amazing that is.

Rachel, what would you say was the key breakthrough that allowed sort of these incredible results that we're seeing?

Yeah, I would I always bring it back to the patient community. The Huntington's community themselves are one of the most hyper vigilant and organised communities.

Most well read up on everything to do with their disease, how to organise and how to best be involved with clinical trials.

So their engagement with natural history studies, all those.

I think it's over 10,000 people who signed up for every year they go and they get certain measurements made.

And if these people hadn't done that, we wouldn't have been able to do this trial. And to make this comparison.

I think that's a really amazing thing.

And it's not just the folks who have Huntington's disease. It's all their carers, their partners, who drive them to these appointments with their clinical neurologists.

That is what has really enabled things for this community, in my opinion.

Terry, you know all about this type of struggle. Your son doesn't have Huntington's disease, but can you tell us a little bit about your son's journey?

Yeah. Mikal had has SPG50 or spastic paraplegia type 50. We were told, go home and love him. He'll be paralysed from the waist down by the age of ten. Quadriplegic by the age of 20. He'll never walk. You never talk.

We went home and lost our minds. That evening, I locked myself in a room. 24 hours later, we realised that we could do something that gene therapies and ASOs or antisense nucleotides, there was therapies that could be done.

And a month and a half later, I flew around the world. I met all the experts in gene therapy. We hired a team in Dallas, Texas, and we started doing this therapy for Mikal.

This, they call it a proof of concept, proof that you can create a therapy.

About a year later, we showed that it would work. It was working in mice. It was working in cells, and we had to raise $4.5 million.

At that point, our community in Toronto came together. We raised $4.5 million over four years, and we were able to safety test the drug, make the therapy, and treat Mikal. In March of 2022.

We have some photos of Mikal that I want our viewers to see. How is Michael doing today? When was this this photo taken?

This photo was taken well before his therapy. He had a major seizure that lasted about three hours.

Wow. And they didn't think he was going to survive. And this is him waking up from that crazy seizure.

We have some photos here as well.

Yeah, that was when Michael was 12 months of age when they diagnosed him with this disorder.

Well, they didn't exactly know what it was, but they diagnosed him with microcephaly.

We went to Greece for a pilgrimage to try to pray away the disease.

And. Yeah, this was just this is him. He's a happy little kid.

How is he today? Is this?

Yeah. He's good, you know, he's-- Michael was the most severe child in in the disorder.

But he's able to communicate with us, tell us what he wants. He hugs and kisses us. He shows affection. He's able to stand. He's improving.

But he was the most severe. There's a spectrum of disorder. Right? Right. And so he probably will never walk. We hope that he'll talk someday.

But if he's able to tell us that he's in pain or he wants his diaper changed, or if he wants to go to bed, then when we're gone from this earth, we'll have we'll have a one. Yeah.

Rachel, what do these results tell us about the current state of disease fighting medical research?

I think we're in a really exciting phase of drug discovery and finding treatments for diseases which have often been overlooked because they're not seen as commercially viable by really large pharmaceutical companies.

Now, we have technologies that allow us to almost copy paste for different types of disease and to create therapeutics, hopefully for many, many people.

That's such an exciting place to be in our society now.

There's a lot of excitement in gene editing tools. We've heard technologies like CRISPR, CRISPR, but in terms of this Huntington's treatment, it did not involve that.

Tell us a little bit about the technology you touched on a little bit, but tell us a little bit about the technology.

Yeah. So this therapy is delivered like many other gene therapies through this harmless virus.

The drug itself is called AMT 130. The virus packages the instructions for something called a micro RNA.

This sticks onto the huntingtin message molecule. This is kind of the in-between of our DNA genetic instructions and the proteins that they encode.

And we have these message molecules that kind of are the in between of those, so that we can faithfully copy the DNA and turn it into protein.

And so this micro RNA sticks on to that message and then stops the protein being made.

And so that's the technology.

And so you can imagine that now we know how to do this for different diseases. We might find another disease where we want to switch off another gene or turn down the levels of another protein.

Terry, even when the science is promising for diseases like this, there are obviously some real barriers. You you mentioned a number there for 4 million. That's just one side of the conversation there. But tell us a little bit about the barriers that that families are facing when it comes to these diagnoses.

Yeah I mean we're not meant to create therapies. Our family is not meant to raise $4.5 million. Do toxicology and animals find a manufacturer? This is not something we should be doing.

And that's the barrier that we have. Is that because they're not commercially viable, that companies are not going to spend $1 billion to make a therapy like this?

There's no interest. And that's why when I had to quit my job and start a pharmaceutical company or.

With no medical background.

Correct, no medical background at all. Well, I have smart people around me. So, you know, it was a team effort. It wasn't just me. It was hundreds of individuals.

And now I have a team of people that are much smarter than I am to get these programs to the clinic, show that they work, and then move them towards approval.

There'll be hundreds over the next 20 years, there'll be thousands of children, and they could have been treated with this therapy, and they will not have unless we get it approved.

Can you help us understand how rare these diseases are? Like Michael's condition? How many people in the world?

Have so Mikal Michael's one of 130 in the world. He's the only child in Canada.

If you put it in perspective, there's 10,000 rare diseases. 5% of them have a therapy of any sort.

And 400 million people in the world have a rare disease. 1 in 10 of us will be affected.

So someone that you love, you know, will have a rare disease Parkinson's, ALS, Alzheimer's, sickle cell anaemia, haemophilia.

Someone you know has a rare disease or will have a rare disease.

When you were starting your family, you. I imagine you didn't think that this was what the fight that you were going to be fighting, that you were going to be an advocate for treating rare diseases. What other changes are needed to be successful in this fight?

From an individual perspective when you're in this? Yeah, well, I was an introvert. Doesn't show it anymore. But once you do 100 interviews, you know, kind of breaks you afterwards.

But you have to have a strong will. You know, we were when we first put out our story, people were telling us to put down Michael, that he's, you know, that he doesn't deserve to live.

And you have to have a strong backbone. You have to have a strong will. You have to have a never give up attitude, and you have to have a support community around you.

And luckily, I have an amazing wife and amazing children that supported us, an amazing community that came on and said, we are not going to let Michael's have this disorder. We're going to be here for you.

And then we were fortunate enough to meet amazing people along the journey to help us do what we needed to do to get there.

It was, again, it's not meant for families to do this.

I have to imagine that you get emails, phone calls, messages from families who were in a similar situation than you were.

I get 15 calls a week. I had two just on the way here.

It's non-stop because families are trying to save their children and they see my story and they want to do what I did, and some of them are successful and some of them are not.

And it's something that we have to figure out. We have to figure out a path forward.

Thankfully, technology is changing rapidly, and what we thought was non-curable ten years ago is curable now, and if our children were born five years from now, it would be a different story.

We'd have probably therapies right off the bat.

Some things we need to do are newborn screening.

We need to have genetic screening for every single child that's born.

That way, when a drug is in the clinic, we can treat a five month old, a two week old, A111 month old, and those children will be more towards a cure than a treatment.

Because as you can imagine, it's like a sliding scale. If we catch them early enough, it'll be more towards a cure.

If we treat them at 17, it's less and less of a cure, more and less and less of a treatment even.

Right. So that's where we have to really step up. And government has to start really investing in this new technologies and new innovations.

Rachel Terry had mentioned a path forward. So I'm curious, how can the lessons learned in the Huntington's case apply to the way we treat genetic diseases in general?

Yeah. Well, I think doing any of exactly the work that Terry discusses like this is hard and it's quite difficult.

We need the community to mobilise both scientists and government to allow us to find new paths for how can we get drugs from ideas that scientists have in the lab, to things that we can test and develop in the clinic to into?

The most important part of this is getting the drugs to the patients.

And one of the biggest barriers that we can kind of foresee with gene therapies, in particular, is the barriers for how you actually run the clinical trials, how you actually get approval and then how expensive those drugs are at the end.

Typically, we're talking in the order of maybe 1 to $5 million per patient, and how Health Canada and other approval agencies are going to oversee, administer that and ensure that people can actually be treated with drugs that are maybe already available, but they're just so expensive.

So that's going to be a problem we've got to figure out.

What kind of diseases might be in line next.

Yeah, it's a great question. I think I really like that Terry brought up this statistic that 1 in 10 people in the world have a rare disease.

And so these are all kinds of different things. Some of them we really don't understand.

We don't really know if they have a genetic basis or if it's some other environmental factors or something else altogether.

But I think at least those with a defined genetic basis, there's a very obvious path forward for how we can use some of these emerging technologies with gene silencing or CRISPR or other kinds of editing technologies to try and find viable therapeutics.

And I think that's where things are looking really exciting in the next 5 to 10 years.

All right. My last question to both of you, Terry, we'll start with you. What's your one hope for the future of genetic medicine in the next, say, 5 to 10 years?

My hope is that the technology has evolved to a certain point where a child is born, we do a genetic screen within a day, and on day two, they're getting treated.

And I think we're not far from that. I think in the next 5 or 10 years that will be will be eradicating disorders.

And that's why I say Mikal was just born a bit too early. You know, if he was born five years from now, he would have been cured.

Unfortunately, he was born now and we had to do what we can. But that's our hope is that that we eradicate these, these disorders so that our loved ones will never suffer from these diseases.

Rachel, you get the last word.

Okay. I think something that's really exciting with these technologies is the underlying science didn't even exist maybe ten, 15 years ago.

And so it makes me so hopeful about what is currently in the lab, like what scientists at University of Toronto and other places around the world, what they're developing and what possibilities they offer for the future.

I don't think we even know what technologies will exist that could enter the clinic in the next 5 to 10 years, and that's really exciting.

Very exciting times. Rachel. We're going to leave it there. Thank you so much for your insights, Terry. Thank you so much and wish your family all the best.

Thank you so much.

We appreciate you.