Taking aim at rare diseases

JAX Professor Robert Burgess and collaborators are developing personalized gene therapy for Caroline Fletcher, a Texas child suffering from a rare neuromuscular disease. Photo by JON SHAPLEY/HOUSTON CHRONICLE.

Taking aim at rare diseases

It’s just not fair. One measly gene — out of more than 20,000 — goes wrong, and a newborn baby faces a future with a disease that could hamper her mobility, make breathing a struggle or even end her life. And it doesn’t help that a given genetic disease may be so rare there are only a handful of cases in the world.

By definition, a rare disease is one that affects fewer than 200,000 individuals in the United States. Because of the small population afflicted by any one illness, funding to investigate causes and treatments tends to be limited, slowing the discovery of potential therapies. Yet with over 7,000 recognized rare diseases, an estimated 350 million people worldwide are affected at any given time.

New treatments for rare diseases are here

Teams of scientists and clinicians, armed with technologies that use laboratory mice to fast-track drug discovery and testing, are coming to the rescue. In just the past few years, several new treatments targeted at rare genetic diseases have come available:

December 2017: The U.S. Food and Drug Administration approved the first drug to treat children and adults with spinal muscular atrophy (SMA): nusinersen, produced by the Biogen pharmaceutical company as Spinraza. In clinical trials, children who normally would have succumbed to their disease were not only alive but reaching major developmental milestones.This successful therapy derives from a mouse model developed by Cat Lutz, Ph.D., director of the Jackson Laboratory (JAX) Rare and Orphan Disease Center, in collaboration with the SMA Foundation and researchers at Columbia University and Regeneron Pharmaceuticals Inc.

December 2017: The FDA approved the first gene therapy for a genetic disease. Spark Therapeutics’ Luxturna™(voretigene neparvovec-rzyl) is a one-time gene therapy for treating children and adults with the rare inherited blindness disorder biallelic RPE65 mutation-associated retinal dystrophy. The foundational work for this treatment, including the viral vector used to deliver the therapy, was developed in a mouse lacking RPE65 by a research team including JAX Senior Research Scientist Bo Chang, Ph.D.

November 2017: The FDA approved Mepsevii(vestronidase alfa-vjbk) in November 2017 for use in pediatric and adult patients with mucopolysaccharidosis type VII (MPS VII), a progressive condition that affects most tissues and organs and affects fewer than 150 patients worldwide. The disease is often referred to as Sly syndrome for William Sly, M.D., who first described MPS VII and worked with a JAX team to characterize a mouse model for the disease.

May 2017: Another Radicava (edaravone) became only the second FDA-approved treatment available to reduce the progression of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease theat typically strikes in middle age. Preclinical work in ALS mouse models showed that edavarone suppresses motor functional decline.

August 2018: The FDA approved Galafold (migalastat), the first oral medication for the treatment of adults with Fabry disease. Fabry disease is a rare and serious genetic disease that results from buildup of a type of fat called globotriaosylceramide (GL-3) in blood vessels, the kidneys, the heart, the nerves and other organs.

These successes start with advances in genomic testing and sequencing. “The pace of discovery of the genes responsible for rare diseases is proceeding at an extraordinary rate,” says David Valle, M.D., director of the McKusick-Nathanson Institute for Genetic Medicine at Johns Hopkins Medicine. “This has been accompanied by enhanced genetic testing in the clinic so that, for 30 percent or more of these previously difficult to diagnosis patients, we are now able to make a rapid and precise molecular diagnosis. This informs management, prognosis and recurrence risk and, increasingly, due in part to the incredible power of mouse models, leads to the development of innovative and effective treatments.”

Once the relevant mutation has been identified, the next step is to “put it into a mouse.” That’s where the world-changing CRISPR-Cas9 gene editing technology comes in. The process of creating new mouse models for diseases once involved tedious cross-breeding protocols that could take months or even years, and there was no guarantee that the sought-for mutation would “take.” CRISPR enables researchers to precisely engineer specific genetic mutations in a mouse in a single step.

The JAX Rare and Orphan Disease Center brings these technologies together and provides a start-to-finish approach to understanding the genetic basis for rare inherited conditions. “We partner with foundations, pharmaceutical and biotech companies, and other scientists worldwide to facilitate research into treatments of these less common diseases,” says Lutz.

Cat Lutz, Phd is the Director of the Rare and Orphan Disease Center at The Jackson Laboratory. Lutz and her team develop preclinical mouse models of neurodegeneration to test therapeutics and inform clinical trials. Photo by Sean Harris.

Families are catalysts for rare disease discovery

But before the FDA approval, before the clinical trials, even before the mouse model development, these new therapies for rare diseases typically start with the people who have the strongest motivation: patients’ families. JAX may be the only “hit” patient families get when they search online for research programs in a specific rare genetic condition. That’s because the chances are great that the culprit mutation is in a JAX mouse model. “No institution in the world can match the genetic diversity of the JAX mouse population, or the expertise in mouse model development, for diseases including rare and orphan diseases,” says JAX Associate Professor Greg Cox, Ph.D. Cox studies neuromuscular diseases with a focus on SMA and its very rare variant, spinal muscular atrophy with respiratory distress (SMARD), as well as ALS and Duchenne’s muscular dystrophy (DMD).

“Mice that develop the same disease symptoms as patients, and that carry mutations in the same genes, enable researchers to test many different therapeutic strategies in a relatively short time,’ Cox explains.

Eric Sims, a University of Notre Dame associate professor, and his wife, Jill, are the parents of two children born with SMARD. One of Sims’ students organized a fundraiser to raise money for SMARD research after identifying the Cox lab online. Eric’s parents, Grant and Patty Sims, then connected with Cox to learn more about his SMARD research program, and subsequently established the Sims Family Fund for SMARD Research at JAX.

The parents of a girl with a mutation in a gene called KIF1A that causes a severe neurological disorder reached out to JAX. They are among the founders of KIF1A.org, which is running a #weneedamouse campaign to fund mouse model development. “Our friends at Jackson Lab are some of the most supportive people in the world,” the KIF1A.org website states. “These scientists care about our families and our KIF1A children.”

Caroline Fletcher, age 7, was diagnosed with a hereditary degenerative nerve disorder designated CMT2D, a rare variant of Charcot-Marie-Tooth (CMT) disease. Fletcher’s grandparents contacted JAX, and now JAX Professor Rob Burgess, Ph.D., director of the JAX Center for Precision Genetics, tested a novel gene therapy on mice that mimicked Caroline's disease, following successful experiments in a JAX-developed mouse model of CMT2D. Burgess and his team saw notable improvements in the mice, and now an expert team at Nationwide Children's Hospitaly is seeking FDA approval for Caroline to use this experimental treatment.

The parents of Talia Duff, a 13-year-old Massachusetts girl with CMT4J, a different variant of CMT, started the CureCMT4J Foundation, which met its grassroots fundraising goal of $1 million in 2017. Lutz and the JAX team made a custom mouse model for Talia’s genetic disease. Lutz's team then tested a new gene therapy on the mice and saw very promising results. The mice survived longer and all of their fine motor functions improved. Now, Lutz and her colleagues are working with the FDA on a clinical trial design.

Yet another family contacted Lutz in hopes of pursuing research in Snyder-Robinson syndrome (SRS), a rare developmental condition, and organized the Snyder-Robinson Foundation to raise funds for research and provide resources for families of SRS patients.

A 2017 Wall Street Journal article about the struggles of families pushing for a cure for rare diseases quotes Lutz: “We are trying to develop a system of resources that patients and their families can plug into so they do not have to shoulder the expense of this. But, we are not there yet.”

Yet, Lutz says, there have never been greater possibilities to find treatments for rare genetic diseases.

“A colleague once asked me why I was working so hard on a rare disease like SMA to benefit so few patients,” Lutz recounts. “The fact is, all the things we learn from these rare and orphan diseases will be applicable to Parkinson’s, Alzheimer’s and other diseases with bigger patient populations.

“And when you see kids with SMA actually walking and playing, who without treatment probably would not even be alive, that’s why we work so hard,” she says.