After decades of frustration watching seemingly healthy babies lose their power to roll over, sit up or eat, Richard Finkel, MD, was amazed.
A new drug was changing everything for children with spinal muscular atrophy (SMA). This previously untreatable neurologic disease withers nerve cells in the brain and spinal cord.
“We started seeing one child after another sit up and roll over — things these babies never, ever achieve,” he recalls. “Several years later, we see these children continue to improve. Now we’re starting to think about them growing up and becoming teenagers and young adults and facing the world, where none of this was ever possible before.”
Finkel played a vital role in testing what eventually became three successful drugs for SMA, which often killed affected babies by their second birthday. Now he’s bringing that life-changing insight to St. Jude Children’s Research Hospital as he creates a model for treating SMA and scores of other neurologic diseases that affect babies and children.
We’re moving in a new direction, perhaps,
but staying true to the core values and mission of St. Jude.
Finkel is director of the Center for Experimental Neurotherapeutics, the clinical component of a new St. Jude program called the Pediatric Translational Neuroscience Initiative (PTNI). Unlike other pediatric neurological programs, the PTNI joins lab and clinical research, local and international collaborations, and partnerships with drug companies to bring promising treatments to children with neurological diseases.
Launched in 2020, the PTNI will also test current treatments to gauge their safety and effectiveness in children at St. Jude and beyond. This initiative joins the hospital’s renowned programs for catastrophic childhood diseases such as cancer, sickle cell anemia and HIV. Neurologic diseases are just as big a burden, even though therapies had been limited until recently by poor understanding of their causes.
“We’re moving in a new direction, perhaps, but staying true to the core values and mission of St. Jude,” Finkel says. “It’s a chance to be bold in steering St. Jude toward other catastrophic diseases affecting children where there’s a high unmet need and opportunity to hopefully find cures and save lives.”
The time is now
About 1 in 6 children have some form of neurological disability, ranging from seizures to movement disorders to neuromuscular diseases. Some of those disorders can thwart a child’s ability to talk, see or hear. Like SMA, almost all of these diseases are driven by a mutation or change in a single gene. This trait makes them ripe for drug treatments that have recently emerged to target wayward genes and block the disease process.
For most of these conditions, current treatments either don’t work or only manage symptoms without fixing the underlying problem.
“These are substantial disorders that limit the ability of these children to function independently or become adults who can function effectively in society or at home,” Finkel explains. “They’re often unable to get jobs, they struggle with relationships, and in the most severe conditions, these children have reduced survival. Unfortunately, with some of the conditions I’ve dealt with, more than half the babies don’t make it through infancy.”
We want to map out the conditions where we can have the most impact because of critical gaps, or because the companies developing those therapies don’t know what to do once they have the therapy in hand.
Chart the course
PTNI started as a St. Jude–funded blue-sky project of bold ideas to transform science and medicine. But the program was years in the making. The vision of J. Paul Taylor, MD, PhD, chair of St. Jude Cell and Molecular Biology, the initiative comes in an era when key developments have merged: Not only have scientists cracked the genetic cause of many pediatric neurologic conditions, but promising treatments have surfaced to target those genes.
Taylor, director of PTNI, was an integral part of research that pinpointed the genes responsible for children’s neurologic syndromes and figured out how they cause illness. Today, next-generation gene sequencing is helping researchers find the genes that cause individual conditions. Meanwhile, drugs have been developed that can deliver their effects straight to the brain through innovative techniques.
Discoveries in the lab
The basic research component of the PTNI is called the Center for Pediatric Neurological Research. Led by Peter McKinnon, PhD, of St. Jude Genetics, scientists in this program will make discoveries that can be translated into cures.
“It’s always been clear that the mission of the hospital has been to tackle catastrophic diseases. If you want an example of a catastrophic disease, you need look no further than inherited neurologic diseases,” McKinnon says. “Our work will have a really profound impact on families affected by these disorders.”
He explains that treating children with neurological diseases is fundamentally different than treating those with cancer.
“With cancer, you basically want to get rid of the cancer by killing it,” he says, “so the strategies are to develop agents that target and destroy the cancer. To some extent, it’s the opposite with neurodegenerative diseases. You want to prevent symptoms from occurring; you want to save the tissue. It’s important to intervene as early as possible before anything bad has happened.”
McKinnon has conducted extensive research into movement disorders associated with the cerebellum, the part of the brain that affects muscular activity. One of his newest colleagues, Heather Mefford, MD, PhD, studies the genetic causes of childhood epilepsy. Another team member, Andy Kodani, PhD, focuses on the development of the cortex, a brain region that plays a key role in activities such as attention, perception and memory. McKinnon is currently recruiting additional scientists who will add breadth and depth to the program.
If you want an example of a catastrophic disease, you need look no further than inherited neurologic diseases. Our work will have a really profound impact on families affected by these disorders.
Highest chance for cures
Hoping to speed new and different treatments from the lab to the clinic, Finkel and his St. Jude colleagues are launching several clinical trials this year.
Children in these studies will be treated by a dedicated team of doctors, physical and occupational therapists, and specialists such as pulmonologists and surgeons.
The first such study will take a closer look at one of the drugs already approved for children with SMA, but in an age group that hasn’t been studied — newborns. These babies will be screened at birth with a test that reveals SMA before symptoms such as muscle weakness occur.
“Treating them before they show symptoms offers them the highest chance of a cure,” Finkel says. “We know this drug works well in infants and children who show signs of weakness, but it doesn’t cure them. Hopefully this study fills that gap.”
Other clinical trials will focus on Duchenne muscular dystrophy, the most common and severe form of muscle-weakening disease; and another genetic condition called Friedreich’s ataxia. There are currently no effective medications for Friedreich’s ataxia, which causes problems with speech, swallowing, hand control and walking.
Some trials will also include children who have been left out of prior research, whether because of age or disease severity, but who still might benefit from therapy, Taylor says.
“We want to map out the conditions where we can have the most impact because of critical gaps,” he adds, “or because the companies developing those therapies don’t know what to do once they have the therapy in hand.”
A center without walls
Partnerships and collaborations are crucial to the success of this new venture. Local partners include the University of Tennessee Health Science Center and Memphis-based Le Bonheur Children’s Hospital, whose neurology department has expertise in epilepsy and disabilities related to brain development.
Input and efforts by drug manufacturers, global experts, patient foundations, outside institutions and other St. Jude departments will create a “center without walls” to ensure all goals are met.
“It’s impossible to do all of this at St. Jude,” Taylor says. “There are so many diseases and so many ways one could develop therapies. The smartest thing to do is make this a global effort.”
Finkel hopes in the next five years to recruit more physician-scientists to the program and explore a dozen or more neurologic diseases. To Taylor, big-picture success requires “systematically churning out effective therapies for kids with neurological diseases.”
Success might mean providing proof that current treatments also work for other age groups or can be stopped after a certain age without patients getting worse, Taylor says. It also means creating treatments that never before existed.
“I want to see us change the standard of care for kids who are currently just supported with things like slings, braces and surgery,” Taylor says. “If this initiative is successful, we will see kids treated differently than they are today.”
“This is clearly at the very center of our mission to address catastrophic diseases of childhood,” he says. “There is no other place that’s stepping up to fill this unmet need.”
From Promise, Spring 2021