Neurology Today: “Advocacy for Neurological Disease: The ‘Family Business’ No Family Wants”

By Gina Shaw

They don’t have MD or PhD degrees. They don’t run research laboratories, direct hospitals, or oversee major academic medical centers. Yet they have helped changed the course of neurological research, driving tens of millions of research dollars – both private and federal – into the quest for treatments and cures for diseases that, until recently, had been virtually ignored, if not unknown.

These are the families of children with complex, little-known neurological disorders like spinal muscular atrophy (SMA) and Rett syndrome. Within the last two decades, especially Dinakar Singh and Loren Eng as the Internet has provided unprecedented research became active advocates for capabilities to anyone who can get to a computer, these SMA in 2001, when their two- groups have become powerful, effective, organized players year-old daughter Arya was in the world of biomedical research funding. diagnosed with the disease.


”When you have families whose arms are empty prematurely, or who watch their children struggle with every aspect of their daily lives, you have desperate people,” said Audrey Lewis, founder of Families of SMA (FSMA), the largest international organization related to the disease, which is the number one genetic killer of children under the age of two. Although it strikes one in 6,000 newborns in the US every year, roughly the same prevalence as amyotrophic lateral sclerosis, SMA has received relatively little public attention.

Despite that “orphan” status, FSMA has raised $16 million in research funding since 1984, and helped convince NIH to ramp up its support for SMA research from under $1 million in 1998 to $5 million in 2002. Many of the major genetic breakthroughs in the study of SMA have been largely supported by FSMA funding – including the Ohio State University research that first identified the genetic locus of the disorder, the deletion of the Survival Motor Neuron (SMN1) gene on chromosome 5.

Today, SMA seems tantalizingly close to a treatment. Scientists at the University of Utah, funded in part by FSMA, are studying two already-available drugs, sodium phenylbutyrate and valproic acid, the first drugs that have shown an ability to boost the deficient SMN protein.

FSMA has also partnered with industry, supporting high-throughput screening by Aurora Bioscience and drug discovery work by pharmaceutical companies deCode Genetics and Paratek Pharmaceuticals, attempting to boost the expression of the SMN gene’s backup, SMN2. They have developed an international patient registry that identifies patients willing to participate in the clinical drug safety trials that FSMA has helped to sponsor. And their 8th Annual Research Conference, held in Chicago last June, attracted some 80 scientists with an interest in the disorder.


Loren Eng and Dinakar Singh became active advocates for SMA in 2001, when their twoyear-old daughter Arya was diagnosed with the disease. Soon they and their families were making the rounds on Capitol Hill. “Senator Tom Harkin said to us, ‘How is it possible – with what you’re telling me about numbers, impact, and scientific promise – that I’ve never heard of this disease while sitting on health appropriations committees for the past 20 years?’ If he hadn’t heard of it, we were pretty sure no one else had heard of it,” said Ms. Eng.

Galvanized, Ms. Eng and Mr. Singh created the Spinal Muscular Atrophy Foundation, which combines research funding for SMA with awareness and advocacy campaigns aimed at policy makers and the public. “Awareness drives research dollars, and we wanted to push the federal government to invest in the disease, based on its impact on children,” said Ms. Eng.

Last year, the work of FSMA and the SMA Foundation yielded perhaps its most impressive achievement yet: convincing NINDS to designate SMA as a model for a new translational research program, aimed at developing effective drug treatments for the disease within as little as five years.

“It took years of knocking on doors,” recalled Ms. Lewis. “We went through four directors: Zach Hall, Audrey Penn as Acting Director, Gerry Fischbach, and now Story Landis.” ”It’s a work in progress, an experiment; they have never done this before,” Ms. Eng said. “We hope they come up with a treatment for this disease. If they do, it can be used as a model for drug discovery in other neurological diseases.”


But making their case at NINDS and on Capitol Hill wouldn’t have done much had the families not helped bring the research to a critical point. “These families have been catalysts for projects that allowed people to generate preliminary data, which then enabled them to compete successfully for NIH funding,” said Darryl DeVivo, MD, Director Emeritus of Pediatric Neurology, and Sidney Carter Professor of Neurology and Professor of Pediatrics at Columbia University. Dr. DeVivo heads the SMA Foundation Scientific Advisory Board.

“Within less than a decade we have come from knowing virtually nothing about what causes SMA, other than that it’s genetically determined and autosomal recessive, to a point where we know precisely its molecular basis. The timing is wonderfully correct to take such substantial advances and develop effective treatments for this disease.”


That kind of timing is essential for advancing a major investment in disease research, said Allen Roses, MD, Senior Vice President for Genetics Research at GlaxoSmithKline. Best known as the scientist who led the team that identified apolipoprotein E4 as the major gene variation marking people who are susceptible to Alzheimer disease after the age of 65, in the early 1980s Dr. Roses was also a key player in identifying the genetic locus of myotonic dystrophy – a campaign driven in large part by one family.

The Gary family of Denver, CO, shuns publicity for their role in funding the myotonic dystrophy gene-research effort, but Dr. Roses credits them for making it all happen. “This was a time when molecular genetic methods were first being applied to the study of linkage for disease. Myotonic dystrophy was a known autosomal-dominant disease, and it seemed likely that it would be just as good a candidate as, say, Huntington disease for one of the early studies,” he said. “At that time, there were probably only two investigators in the world with a big interest in the disease: one was Peter Harper, in Wales, and the other was me.”

Gary family members were used to charitable giving; patriarch Sam Gary founded the public education-focused Piton Foundation in 1976. When myotonic dystrophy struck their family, Dr. Roses observed, they had the mechanism readily at hand to fund research. “They asked for proposals; mine as to do a linkage study, and I suggested involving multiple centers so that both Peter and I could contribute families to it.” Over the next few years, the national Muscular Dystrophy Association also became involved, and about 10 laboratories participated in the race to identify the gene, which was at last located in late 1991, on chromosome 19.

“These studies would never have been done without the involvement of this particular family,” Dr. Roses said. “We never would have gotten to where we are now if we hadn’t had their support in time for the academic gold rush that followed in the early 1990s. They demonstrated that it could be done, and then the government belatedly got into the act.”


Family groups, working with researchers, help to push the science around a particular disorder to the “convergence point” where larger public investments in drug discovery are worthwhile, agreed Cynthia Joyce, Director of the New York City-based SMA Foundation and former Director of the Academy’s Education and Research Foundation. “These families feel a sense of urgency. It is incomprehensible to them that there is no specific treatment for some of these disorders.”

For years Kathy Hunter didn’t even have a diagnosis, let alone a treatment, for her daughter, Stacie. At about one year old, the beautiful dark-haired girl started regressing, losing motor control and verbal ability, wringing her hands, and flying into inexplicable rages. Doctors who didn’t immediately label her autistic told Ms. Hunter that Stacie was “one of a kind” and that she’d probably never know what was wrong with her daughter.

In 1984, when Stacie was ten, her primary physician, Mary Coleman, MD, a neurologist and founder of the now defunct Children’s Brain Research Clinic in Washington, DC, attended a meeting in France where a new syndrome was described, named for its discoverer, Austrian neurologist Andreas Rett. “She literally stood up and said, ‘That’s Stacie Hunter!’” Ms. Hunter recalled. Stacie became the 36th child in the world identified with the newly-named Rett syndrome.


The Hunters started a support group, launching it with an ad in the Journal of Child Neurology and focusing from the start on working with scientists and funding research. In November 1984, they held their first meeting, bringing together the families of 39 children with Rett syndrome from the US and Canada.

Now celebrating its 20th anniversary, the International Rett Syndrome Association (IRSA) has directly funded $2.33 million in scientific research solely on Rett syndrome and lobbied for nearly $35 million in additional funding. Scientists have called IRSA “a model of partnership between parents and advocates of children with developmental disorders and the biomedical scientific community.”

IRSA’s support, and their enormous international patient database, led to the 1999 discovery that a defective gene on the X chromosome known as methyl-CpG binding protein 2 (MECP2) leads to the disorder. “We knew that we were getting close to finding the gene,” recalled Ms. Hunter. “We went to every lab that we knew was studying the gene and said ‘We’d like to fund a full-time scientist in your lab to devote a full-time effort over the next year to finding the gene.’”

Three months later, IRSA-funded scientist Huda Zoghbi, MD, a Howard Hughes Medical Institute Investigator at Baylor College of Medicine in Houston, struck gold. “Dr. Zoghbi was a charter member of our advisory board,” Ms. Hunter said. “She had been looking for the gene for 16 years and was just about to give up when we met with her. She was the first one to suggest that it was on the X chromosome, and others laughed at her. I told her, ‘Give this one more shot.’” With the gene identified, mouse models have been developed and downstream genes are now being studied.

MECP2, notes Ms. Hunter, is a “housekeeping gene,” switching on and off a vast array of downstream functions. “Obviously, this gene plays a very important role in brain development. This mutation has been found in females with mild mental retardation and males with similar retardation, in people with schizophrenia and bipolar disorder, and people with autism,” she said. “We call Rett the Rosetta Stone of neurological disorders. Rett studies will affect all these disorders that affect millions of other Americans.”


Parent advocates like Audrey Lewis, Loren Eng, and Kathy Hunter have become quite literate in the science behind these genetic disorders. “I’ve learned far more from these family advocacy groups over the years than they have learned from me,” said Dr. DeVivo. “Many of them become extraordinary students of the disease in a short time. They live this disease every day, every waking hour. They have an insatiable appetite for knowledge.”

Of course, not all family groups – no matter how well versed in the science – find themselves at the same promising point in research that SMA finds itself now, and where Rett syndrome may well be soon. “There are certain diseases today for which we don’t have the foggiest idea what the basic mechanism is,” said Dr. DeVivo. “So it’s very hard to think about research projects focused on developing more effective treatments or cures when you have no real insight into the genetic or molecular basis for the disease.”

But other groups, with a longer path ahead of them, can adopt a similar model. “If you follow a path that’s fairly well outlined now, starting with finding a platform to do the research – a gene is often a good start – you can begin to advance research in ways that you haven’t done before,” said Ms. Joyce. “But you need a hook, a result in the science, to take that next step.”