SPG-15: A Mother's Fight for a Gene Therapy Cure, Maddi's Story

Thought LeadersCarina ThurgoodCEO of The Maddi FoundationThe Maddi Foundation

News Medical spoke to the CEO and founder of the Maddi Foundation at the Charles River Gene and Cell Therapy Summit to gain a patient perspective on the impact gene therapy research can have. Maddi Thurgood is the only person in the UK diagnosed with Spastic paraplegia 15 (SPG-15) and is one of 100 worldwide.

Maddi's mum, Carina Thurgood, continues pushing to raise awareness of SPG-15 to advance research and development of a Gene Therapy for this rare disease. Thrown into the deep end of the world of rare diseases, cell and gene therapy research, and fundraising, Carina has defied all odds in the search for a therapy for her daughter.

What is SPG-15?

Maddi suffers from a rare disease known as autosomal recessive spastic paraplegia type 15 (SPG-15), a complex and ultra-rare form of spastic paraplegia. The condition is often characterized by childhood/adulthood onset of progressive lower limb spasticity, often associated with mild intellectual disability, cerebellar ataxia, peripheral neuropathology, and retinal degeneration.

SPG-15 is a recessive disease passed down from both parents to their children. Thus each parent carries a variant in one copy of the ZFYVE26 gene. At the molecular level, SPG-15 is caused by the loss of function mutations in the recessive gene. These mutations encode the protein spasitizin, which regulates endosome and autophagosome reformation.

Spasitizin interacts with the protein spatacsin and a complex containing AP5Z1, all of which are vital in the function of endosomes and lysosome homeostasis. Mouse models have shown that mutations in the ZFYVE26 gene lead to an accumulation of vesicle-like structures, which leads to the degeneration of nerves and causes typical symptoms of neurodegenerative diseases

Symptomatic and rehabilitative treatments are the only treatment pathways available for patients at this minute in time. In the hopes of changing this for her daughter, Carina started the Maddi Foundation to raise funds to support research trying to tackle SPG-15 at the source, the gene.


Please introduce yourself, tell us about your career background, and provide insight into what led you to be here today at the gene and cell therapy summit?

I am Carina Thurgood, the founder and CEO of the Maddi Foundation charity.

However, my background started very differently. Originally, I was a commercial florist in London, where I would travel to various big hotels in and around London and do all the grand displays there. So, I have no scientific or medical background whatsoever.

The reason I'm here today at the gene and cell summit is that my teenage daughter, Maddi, developed an ultra-rare illness when she was 15. Because it's so rare, with her being the only one with the disease in the UK, it was up to me as a mum to try and find someone to help her.

Since Maddi was diagnosed, I have worked with scientists to try and find her treatment. Today's aim is to try and spread awareness for her ultra-rare disease, known as SPG-15, in the hope that someone here can help us fight for my daughter.

You are the founder and CEO of the Maddi Foundation. Please tell us more about the Maddi Foundation, its aims, and why it was founded?

The Maddi Foundation was founded in 2017. Before then, I had connected with a gene therapy specialist here in the UK, where I was looking for treatment for my daughter. This is where I realized the imminent need for funding to allow this research to take place.

Despite our fight, the disease is so rare that no NHS or government funding could be available for someone like my daughter to find a treatment. In turn, I had to look in a different direction.

So, I began raising funds to facilitate research into the disease, and while raising funds, I thought, "Well, I might as well start a foundation." And that's where the Maddi Foundation came in.

Please discuss Maddi's journey with SPG-15, her symptoms, and how this has impacted her and her family's life?

Before Maddi was diagnosed at 14, she would ice skate and live like a normal active child. Little did we know that her future was about to change massively. At 14, I noticed Maddi walking with a slight limp; I just thought she had developed a 'teenage swagger'. 

However, she started falling and tripping up often, so I took her to the GP who had no answer about why this was happening. Maddi's diagnosis journey began at Great Ormond Street in London, where she had an MRI that revealed signs of a genetic disease. 

After a long, emotional process, we discovered that Maddi had an ultra-rare genetic mutation, SPG-15. 

We were told about the symptoms, which include paraplegia, quadriplegia, and juvenile Parkinson's disease. We were honestly just heartbroken and confused. What was even more heartbreaking was being sat down and told that there was no treatment, only symptom management.

The impact is huge. Imagine being told you have a rare disease that will lead to life-limiting symptoms, and nothing can be done about it. From a mum's point of view, you just feel helpless.

This is why I started my pursuit of finding a cure for Maddi. I quit my job and started doing my own research. I spent my days reading papers and medical journals whilst reaching out to copious amounts of researchers across the globe. We finally connected with Professor Azzouz at the University of Sheffield, who agreed to aid us in our fight for Maddi. 

Funded solely by our fundraising efforts, Professor Azzouz now leads the gene therapy research aiming to develop a therapy for SPG-15. However, more funding is needed to push research to the next stages. 

Maddi speaking on ITV interview about her journey with SPG15 -Hereditary Spastic Paraplegia 15

What is gene therapy, and how important is it in potentially preventing or treating neurodegenerative diseases like spastic paraplegia type 15 (SPG15)?

SPG-15 is a recessive genetic disease, so it's ultra rare. As such, there is no treatment for SPG-15. Thus, the pathway to go down was to consider the use of gene therapy or gene editing as a potential way to 'fix' the gene causing the issue.

Regarding SPG-15, gene therapy is the only treatment route possible due to its rare nature. The two routes currently being considered by our research team are to replace the gene, which is our ideal, or to alter parts of the gene itself.

Gene therapy is so important to us at the Maddi Foundation. I'm sure it is also so important for other families and individuals seeking treatments for ultra-rare genetic diseases, as it provides hope for a future where these diseases could be cured. 

What's the Difference Between Gene Therapy, Cell Therapy, and Gene Editing?

How important is research to the Foundation, and what research projects are currently being supported by grants from the Maddi Foundation?

Research is so, so important to the Maddi Foundation because where the condition is so rare, there isn't a great deal out there. So, we must encourage researchers to think, "Oh, we might look at that." So that is what we're doing.

I reached out to many institutions; I tried to find someone who might be interested in us and SPG-15, who would spend a little time looking and researching possible treatment routes for Maddi.

As I mentioned before, facilitated by our funding at the Foundation, we were able to support gene therapy research based at Sheffield University. Where the Maddi Foundation is very small, as a small charity, there are no costs that go out of the box, so all the money that comes into our charity goes straight to the research at Sheffield.

In Sheffield, the research team led by Professor Mimoun Azzouz has aimed to evaluate whether viral vectors effectively deliver genes to brain cells. The ultimate hope from this research is that bigger grants may be given to further the research to later stages, moving towards finding a cure. 

The Gene and Cell Therapy Summit aims to connect fellow leaders shaping cell and gene therapy development. What importance do events like today's summit hold for the Maddi Foundation?

These events are so important to the Maddi Foundation. It allows experts to hear our story; hopefully, someone listening will offer a helping hand or know someone who can help.

These events also help us raise awareness of a condition that most people reading this won't have heard of.

Essentially, I hope today that everyone attending, when they watch our presentation, recognizes that there are very rare diseases out there and hears the struggles a family faces. We hope someone can reach out to specialists to help us.

If we don't do that, we don't get any help. And I hope today there may be someone that would like to come and talk to us and say, "Maybe we can give you a little bit of help." If anything, though, it spreads awareness and allows Maddi's story to be shared; all we can do is try.

One of the main objectives set out for today is to allow leading experts and executives in the cell and gene therapy space to navigate and discuss the biggest critical challenges they face. What challenges are often faced in research targeting SPG15?

So, the most significant challenge we face is gaining interest in our disease because it's ultra-rare. We understand there is not really any money to be made, so pharmaceutical companies won't want to come on board because there's not a huge number of patients out there.

A study undertaken by Boston Children’s Hospital in America launched an international registry for the natural history of SPG-11 and SPG-15 patients, with 33 cases recorded globally.

So that is a major challenge. Additionally, our gene alone is a challenge because it's quite a large gene, so it's not as easy to adapt it to the traditional gene therapy vector often used in research.

Another major challenge for us is gaining funding because we have had to publicly fundraise to do this. We can't seem to acquire funding because there is not enough interest out there.

How do you foresee the future of the gene and cell therapy landscape changing over the next decade? What impacts may these changes have on people with SPG15?

I envisage that each year more and more and more technology is evolving, and I see the field advancing. So, I do see a future of amazing gene and cell therapy or possibly other types of treatments aimed at genes and cells targeting rare diseases.

From a personal perspective, when you are in a situation yourself, I have a daughter who's not very well, for us these advancements need to come soon, most likely it's not going to be soon enough to possibly save a lot of her.

So that for us, that is obviously a huge challenge. That's why I am here today. If we could push research faster and then be able to do something that would be great. But obviously each year for each patient with SPG-15, they're deteriorating, and those are years we won't get it back.

We really hope that advancements can take place fast enough to make a difference to Maddi.

Image Credit: LeighPrather/Shutterstock.com

How important is donating and generosity in funding research and treatment efforts to stop the progression and hopefully cure rare diseases like SPG15? How can people on all levels (from companies to individuals reading this) get involved and donate to help the Maddi Foundation?

It's really, really, important to help, donate, or fundraise for a very rare disease like SPG-15. It's extremely challenging for a family to do it all on our own. Any help we can get from others means the world to us.

The more funding, we receive, the more research can be facilitated, and we could get a lot closer to finding a treatment or cure.

We would greatly appreciate it if people would come on board with us and join us on this journey. We urge people to keep in mind that if they had to put themselves in our situation, that it was their child that was living with an extremely rare, life-limiting disease, they would appreciate the support from others.

We have had many people fundraising to help us, and we've had individuals that will go out and just do what they can. Companies can come on board and fundraise, too by running charity balls or fundraising events. Ideally, we would like as many people as possible to donate or even offer to run an event. That would be so greatly appreciated.

Overall, our aim is to share our story and raise awareness, and if people can come along and say, "Hey, we'll organize this event, we do that." All that money is accumulated goes towards our research, and we can get to our goal quicker and help save Maddi.

What's next for you and the Maddi Project? Are you involved in any exciting upcoming projects, research, or events?

At the moment we are waiting for our proof of concept for our gene therapy from the research group in Sheffield. That is really important. We know when we get to that stage, it's then stepping up what we do, as well to go to the next level.

Regarding events, we are constantly trying to organize various events. We are trying to organize our third charity ball, which will be the first post-pandemic. We are constantly aiming to raise awareness and increase funding efforts, which is what we will continue to do this year.

Please visit the Maddi Foundation website to keep updated on our latest events.

Where can readers find more information?

About Carina Thurgood

I am proud to be Maddi’s mum, and I set up The Maddi Foundation after Maddi was diagnosed with SPG15. There is no other charity funding research to cure Spastic Paraplegia Gene 15. I realized our only hope was to start one to raise the profile and awareness of this rare disease. I gave up working in the commercial florist industry to set up The Maddi Foundation with my other daughter Alexandra.                                                                                    

Lily Ramsey

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Lily Ramsey

Lily graduated from the University of Nottingham with a first-class degree in Microbiology in 2021. More recently, Lily has graduated with an LLM in Medical Law and Ethics from the University of Edinburgh. As part of her master's program, Lily focussed her research on public health ethics, with a particular interest in health equity and social justice, more specifically in antibiotic resistance ethics.

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