There are diseases that are known – the ones with slogans and hashtags that come to mind instantly when we hear their name. The ones with awareness months and marathons and commercials on television. And then there are rare diseases — those with names seldom heard, that lack the funding and focus in research. The ones for which the path to diagnosis is obscured, and in the shadows wreak havoc on families’ everyday lives.
Schinzel-Giedion Syndrome (SGS) is one of those ultra rare diseases. To date, less than 150 people have ever been diagnosed with this disease worldwide. This number is limited to the patients and does not include the others whose lives are changed by SGS. SGS is a disease that solely affects children who rarely survive past the first decade of life. This means that parents, siblings, and caregivers navigate life with a medically complex child. SGS robs children of the fundamentals of childhood, and in their place can be constant seizures, organ issues, infections, developmental delays and countless hospital visits.
But, for one family, a beam of hope is emerging from Montreal, Canada, where a groundbreaking RNA therapy project is taking shape under the leadership of Professor Carl Ernst at ɬ. Professor Ernst is the Principal Investigator for the D2R funded project, RNA therapy for an ultra-rare disease. His work sits at the intersection of science and compassion, with a focus on rare neurodevelopmental disorders – including SGS.
The hurdles of rarity
SGS is a multisystem disorder caused by a mutation in a gene called SETBP1. This mutation causes very high levels of the SETBP1 protein to accumulate in the brain and other organs. It disrupts expected growth and communication between genes. This overactive protein interferes with brain and organ development in the crucial early stages of life. This leads to various physical and neurological symptoms. The avalanche of symptoms on a newborn who cannot advocate for themselves is challenging for parents and medical professionals. In addition, its rarity, means there is less information about SGS and the path to diagnosis is far less linear than with more common diseases.
Alexander was four months old when his parents received the diagnosis. His mother, Andrea, recalls the medical team being unable to clarify the next steps, mentioning only that the average life expectancy was 48 months. They left the hospital with uncertainty and a piece of paper listing symptoms and specialists. “Somebody for the kidneys, somebody for his bladder, somebody for his brain, somebody for his bones,” she says. “Each one to treat a symptom, but no treatment for SGS itself.” Without hope for treatment, this family, like countless others navigating life with an ultra-rare disease, felt adrift in open water. Until they learned about Professor Carl Ernst at ɬ and the research his team was conducting.
Precision medicine in motion
Professor Ernst’s lab is dedicated to studying the functional genetics of life-debilitating rare neurodevelopmental disorders, including SGS. For over five years, Professor Ernst has worked directly with the Schinzel-Gideon Syndrome foundation to ensure a patient-centered, translational approach to his research on SGS. As a former one-on-one personal care worker with children with disabilities, supporting children and families has always been at the centre of his work.
Using antisense oligonucleotides (ASO), Professor Ernst’s team successfully reduced SETBP1 protein levels in SGS patient derived progenitor brain cells and SGS mouse disease models. The ability to reduce the level of SETBP1 mRNA holds the potential to treat SGS at its root cause rather than all its symptoms. The progression of this research from the lab to the clinic is supported by D2R’s Translational Impact Research (TIR) program.
The TIR funding program is designed to fast-track a select few large-scale RNA-based discoveries into tangible treatments. One of the few programs of its kind in Canada, the TIR program prioritizes projects that directly address the specific unmet needs within oncology, infectious diseases or rare diseases with a unique approach and justify the choice of RNA-based therapies. With this funding, Professor Ernst’s team, which includes a vast collaboration of researchers and medical professionals from the Montreal Children’s Hospital and St. Justine, will work to manufacture and administer an RNA therapy for SGS. The RNA therapy provides a targeted and precision approach adapted specifically for Alex.
“This is the kind of cutting-edge research the D2R initiative strives for,” says Philippe Gros, D2R’s Chief Scientific Officer “supporting bold science that traditional funding models often overlook.”
Single patient clinical trials are a unique mechanism at Health Canada afforded to researchers and clinicians in Canada for emergent and severe cases such as this one. It allows access to potentially life-saving therapies for patients with limited alternatives. It is a model that prioritizes urgency and compassion without compromising safety. The outcome of this trial, though it is designed to only treat Alex, holds the key for a treatment for all children living with SGS.
Chosen for a reason
To meet the family taking part in this research is to understand the heart behind the science. Rafael, Alex’s father, makes it clear that they are simply parents doing what any parents would do: protecting and advocating for their child. Their day-to-day life is that of two working parents with three children under five — one of whom happens to be medically complex. Their daily routine involves all the typical chaos of parenthood, in addition to monitoring blood oxygen levels and suction. Where others might see difficulty, they see faith. “Alex came to us. He was always meant to be part of our family. We have an amazing pediatrician who has our back. Employers who give us flexibility and health insurance. Access to medical daycares. Supportive families.” Adds Andrea “And we get to be chosen to be in this trial. We are really lucky.”
Families with a medically complex child understand the realities of navigating a healthcare system that can vary drastically from one city to another. Pediatricians who are hard to reach, or who might hesitate to provide referrals – even having a pediatrician feels like luck. It requires parents and caregivers to be the experts on their child’s condition and to be ready to advocate at every turn.
For Alex’s parents that advocacy remains at the forefront of every step of their son’s medical care, including through the clinical trial. The treatment is experimental, but as Rafael points out “With SGS, everything is experimental. From diet changes, to procedures, to the cocktail of medications – you just never know how he’ll react, you just hope for the best.”
From uncertainty to possibility
Though none of this is magic, it is as if the stars must all align to make it happen. “This project brings together a remarkable number of talented people from all walks of academia, from support staff to physicians who will deliver the RNA medication designed in my lab. We will tailor the dose to him, and most importantly, we will tailor outcome measures specifically for him,” says Professor Ernst. “This is precision medicine meeting precision outcomes, just for Alex.”
And the logistics of living in a different country add another layer of complexity to the situation. Alex and his family will have to commute to Montreal from Miami frequently for the durations of his treatments. This means figuring out every little detail, like where to sleep after Alex receives a treatment. “I could sleep on a rock, it doesn’t matter,” says Rafael, “what matters to me is his comfort and his safety.” For his parents, the focus is always on the care for Alex, above all else.
This project is more than a clinical trial. It's about a family’s wish to give their child moments of peace. In his first year of life, Alex averaged 90 seizures a month. Fortunately, those have now decreased to less than 20. Though the hope is that with this RNA therapy, they can be eliminated altogether. The goal is to give Alex what SGS has taken from him and his family; first laugh, first words, first steps. And beyond that, it is about giving those opportunities for every child with SGS.
“Alex being first, means he gets to create possibilities for all the other families,” says Andrea.
Stories like Alex’s are at the core of the D2R. This initiative was created to turn the most promising RNA science into real therapies that reach real people. By supporting researchers like Professor Ernst to act quickly and collaboratively, D2R aims to transform rare disease research and provide families everywhere the chance to imagine a future that is not marred by fear, but by hope.
