Scaling up the assault on rare diseases

Center for Precision Genetics

New five-year NIH grant totaling $10.6M funds JAX center to fast-track treatment-focused research for rare genetic disorders.

The U.S. National Institutes of Health have funded a large-scale, multidisciplinary approach to finding treatments for rare genetic diseases, with a five-year grant totaling $10,625,000 to The Jackson Laboratory (JAX) Center for Precision Genetics

A mutation in a single gene can cause a devastating genetic disease, such as cystic fibrosis, and collectively mutations cause from 7,000 to 10,000 different rare diseases. By definition, a rare disease  affects fewer than 200,000 people, but many represent just hundreds or even dozens of patients. Collectively, an estimated 25 million Americans are living with a rare disease.

Any parent with a sick child faces obstacles, but these compound exponentially when the diagnosis is for a rare genetic disease. In many cases, the challenges begin with what parents in the rare disease community term a “diagnostic odyssey,” to pin down the exact genetic cause and find a clinical team with expertise in, or even knowledge of, the condition. Few research programs specializing in the disease, and little incentive for pharmaceutical companies to develop drugs for such a small pool of patients, mean that there may be few or no treatment options available.

“So much of the burden of pushing for cures for rare diseases has been on the shoulders of parents,” says Cat Lutz, Ph.D.The primary research goals of the Lutz lab involve developing preclinical mouse models of neurodegeneration to test therapeutics and inform clinical trials.Cat Lutz, Ph.D., director of the JAX Rare and Orphan Disease Center. “It’s unfortunate and it’s about time that changed. And we're happy to be part of that change.”

Lutz and JAX Associate Professor  Steve Murray, Ph.D.Dissects the genetic mechanisms of craniofacial development and dysmorphology, and develops new genetic tools and resources for the scientific community.Steve Murray, Ph.D., both experts in mouse models of human disease, are the principal investigators of the NIH-funded JAX The center will use the latest gene-editing technology to develop new mouse models of specific genetic diseases, characterize the models to ensure they reflect the human disease, and make the mice and data available to the worldwide scientific community.

That community — which includes academic researchers, disease-based organizations and pharmaceutical and biotech companies — is involved with every aspect of the center’s work, from proposing which diseases to focus on to developing new treatments.

“This is an outstanding opportunity to expand the scope and scale of our work with our human genetics colleagues,” says Murray, “to support their efforts to discover new variants associated with rare disease, and also to help them build a bridge towards translational models for future therapeutic development. The JAX Center for Precision Genetics takes advantage of the unique resources and capabilities of JAX, working closely with these clinical partners around the country.” 

A recent, successful project at JAX demonstrates the center’s process. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a mutation in a motor neuron gene. SMA comes in four different subtypes, some affecting adults, children and infants. It is, in fact, the number one genetic cause of death for infants, affecting about one in 11,000 births.

In collaboration with the SMA Foundation and researchers at Columbia University and Regeneron Pharmaceuticals Inc., Lutz developed a mouse model for SMA. Insights from this and other SMA mouse models from JAX, enabled the pharmaceutical company Biogen to develop Spinraza (nusinersen), which the U.S. Food and Drug Administration approved in December 2017 as the first drug to treat children and adults with SMA. Today, there are now three FDA approved drugs for SMA.

How will Lutz and Murray determine which genetic disease will be the next SMA? “We will have an open portal,” Lutz says, “so that researchers, patient-based foundations, clinical experts and others can nominate the mouse models they would like us to make. We will work closely with the nominating investigators to develop a custom model creation and characterization plan that best fits with their goals and the scientific need.”

The mouse models will then enter JAX’s state-of-the-art animal facilities for breeding and maintenance as they are prepared for distribution to biomedical and research entities worldwide.

“JAX is the ideal environment for this work,” says Murray. “We have the capabilities in terms of technical skills and scientific expertise, but we also have scale. So we have the ability to bring this all together into a cohesive platform to build and test mouse models for a highly diverse range of rare disease conditions. Our goal is to make our capabilities and resources available to everyone who’s working for new treatments for genetic diseases.”

The Jackson Laboratory Center for Precision Genetics, National Institutes of Health, Office of the Director, Grant Number: 1U54OD030187-01