Two little girls from different parts of the globe who share an extremely rare and debilitating genetic brain disorder have been united by Queensland research aiming to find a breakthrough drug treatment.
Sunshine Coast's Tallulah Whitrod, 3, and Singapore's Alissa Lim, 2, would probably have never met under normal circumstances, but their families have come together in Brisbane as part of a study into their devastating disease, hereditary spastic paraplegia.
Researchers will analyse stem cells collected from inside Tallulah and Alissa's nasal cavities in a quest to find a drug that halts the progression of the disease or, in a "fairyland" scenario, reverses it.
The girls inherited two abnormal copies of the SPG56 gene from both parents, resulting in a type of hereditary spastic paraplegia so unusual it occurs in fewer than one person out of every million.
Tallulah is the only known child in Australia with the "currently incurable" condition and Alissa is the only diagnosed case in Singapore.
So few children worldwide have hereditary spastic paraplegia type 56, that doctors are unable to tell their parents how the degenerative condition will progress or how long their daughters are likely to live.
They are unable to talk, walk or even crawl.
But both sets of parents say the disease has not robbed their girls of the ability to smile and experience joy.
They take solace from their daughters' giggles while simultaneously fearing for their futures.
The families first met online via a Facebook group for families of children with the same type of hereditary spastic paraplegia.
They say finding the group has helped relieve the extreme loneliness they feel, as parents of children living with an ultra-rare medical condition.
"We get to share our knowledge."
His wife, Golden, added: "That connection of just having someone who really knows what you've gone through, and what you're going through, is bonding in a very serious and lasting way."
Amid the grief of raising a child with an uncertain future, research led by 2017 Australian of the Year Alan Mackay-Sim at Griffith University has thrown the families a medical lifeline.
The Whitrods, who also have a son Finn, 5, moved from Darwin to the Sunshine Coast last year to be closer to Emeritus Professor Mackay-Sim's research and have raised more than $500,000 since last June to help fund studies into Tallulah's form of hereditary spastic paraplegia.
'We've got the best of the best'
After searching the world for solutions to Tallulah's malady, they found the top scientists in their own backyard — Australia.
"As a family, we researched hard before we selected our research team," Mrs Whitrod said.
"We've got the best of the best.
"I feel so blessed in a way. I know that a lot of people think that sounds insane to say 'blessed' but these are the cards we got dealt. I just feel so lucky that we've been dealt them in a time when there is hope in research."
Professor Mackay-Sim describes his scientific work into rare diseases as like being a detective, searching for clues to help unlock the key to a mystery illness.
"We all read detective novels. At least, I do," he said. "And it's the mystery of it happening that keeps you going.
The 70-year-old has been studying different forms of hereditary spastic paraplegia (HSP) since 2006 with funding from the Australian-based HSP Research Foundation.
More than 80 types of the condition have been identified, caused by defects in different genes.
Using nasal stem cells, researchers at the Griffith Institute for Drug Discovery (GRIDD) have been able to screen drugs for their potential to reverse the impact of genetic mutations on those cells.
The technique has already resulted in the identification of a drug candidate for a more common type of adult-onset hereditary spastic paraplegia caused by a mutation in the SPG4 gene. They are hopeful of taking the drug to a patient trial.
In that case, Professor Mackay-Sim's team identified an active ingredient, dubbed noscapine, in an approved cough medicine sold overseas.
GRIDD researchers will use the same screening process in a bid to find a drug that can stop the progress of Tallulah and Alissa's disorder.
Drug screening underway
Armed with Tallulah's genetic information and data on the biological mechanisms of known drugs, computational biologist Dr Alex Cristino has used artificial intelligence to select about 3,000 drugs already approved for other conditions to screen for their ability to normalise the girls' stem cells.
"There are thought to be more drugs in the world, at least potential drugs in the world, than there are stars in the universe," Professor Mackay-Sim said.
"We're narrowing that down to a selection of drugs which have already been used in the past."
If they find a hit from an approved drug, that would greatly reduce the time it takes for a human trial to be organised, given it would already have been tested for its safety in human patients.
GRIDD cell biologist Vicky Avery will oversee the drug screening process.
Professor Avery said the girls' stem cells would be compared to those of healthy participants.
"We treat the cells with a drug and compare images taken before and after treatment," she said.
"We are looking at the shape, size and the volume of the cells, plus a number of other different factors, to see whether or not the drugs are changing what the cells look like.
"Combining our image-based data with the computational expertise of Dr Cristino, we are able to rapidly identify potential drugs for further evaluation.
"We're seeking drugs that can modify an abnormal cell to become more like a normal cell in both appearance and function.
While avoiding the word "cure", Professor Mackay-Sim said he was confident of "finding some leads" before the end of the year.
Funding a human trial
If drug candidates are identified, they will then be validated at the University of Queensland's Australian Institute of Bioengineering and Nanotechnology, where scientist Ernst Wolvetang is using a different process to create functioning brain tissue — dubbed brain organoids — from the girls' white blood cells.
Professor Wolvetang said having patient-specific brain organoids would inform the researchers about how SPG56 mutations affected brain development and function.
He will test potential drugs on the lentil-sized organoids, which produce electrical activity that mimics human brain waves, to see whether they improve how the tissue functions.
If they find a drug that can be taken to a human trial, the next challenge will be to fund it.
Patient trials are expensive and extremely rare conditions are often neglected by drug companies and government funding bodies, such as the National Health and Medical Research Council and the Medical Research Future Fund.
"Drug companies are not going to touch it, there's no market," Professor Mackay-Sim said.
But the Whitrods are on a mission not only to find a drug to treat Tallulah's disorder.
They hope the drug screening process being trialled in Queensland can be used to inform future research into finding treatments for other extremely rare conditions, including other forms of hereditary spastic paraplegia.
"Even though big pharmaceutical companies aren't interested in funding something that doesn't give them big bang for their buck, the successful development of the treatments we are working on has real potential to accelerate the search for therapies to treat other types of hereditary spastic paraplegia, none of which has an effective treatment.
"I truly believe that if we can get the backing of the government and the backing of those big companies to help us to find a cure, this will be the stalking horse for many, many cures to come and help many, many people."
The Whitrods have established the Genetic Cures for Kids Foundation and named its first project Our Moon's Mission to help fund research for Tallulah, whose middle name is Moon, and other children with defective SPG56 genes.
Their mission has given some comfort to Alissa's parents, Shannon and Gina, who, despite living in Singapore, considered to have one of the best healthcare systems in the world, have found little support there.
"We've been to playgrounds — other kids are running about and Alissa is just looking at them. It hits me quite badly," Mr Lim said.
"She's starting to lose a lot of her functions. It's quite tough to see her lose her ability to do things."
But after flying to Australia and meeting the Queensland researchers studying their daughter's disease, Mrs Lim said they had found "definitely a lot more hope" after months of doctors "not giving any solutions".
For more information visit ourmoonsmission.org.
