During a virtual event, scientists at The Jackson Laboratory (JAX) discussed the dramatic changes that have taken place in the field of genetics over the past three decades – and how those advancements are allowing us to change the course of diseases that have a genetic basis.
Liu emphasized the power of using mouse models to study . “Our scientists, working together with the larger scientific community, are trying to attack rare disorders by first finding the offending genetic mutation through very powerful technologies of genome sequencing,” said Liu. He said the next step is developing models of disease.
“This is exceedingly important since these rare disorders do not allow us to identify the significant cohort or the groups of patients whom we can actually study. We rely on making mouse models in order to craft the appropriate cures.”
Finding cures for the uncurable
Burgess, who researches the genetics underlying neuromuscular and neurodevelopmental disorders, shared that his lab is not only using mice as a discovery tool, but as a modeling and validation tool. “We take the findings in human genetics and engineer them into a mouse in order to better study the disease and the disease processes,” he explained.
Burgess and collaborators are developing personalized gene therapy for , a nine-year-old with a specific form of a rare disease called Charcot-Marie-Tooth type 2D. This disease leads to degeneration of the motor and sensory neurons that leave the spinal cord and innervate the muscles and sensory nerve endings in the hands and feet. “For this disease and for any form of Charcot-Marie-Tooth disease, there's currently no curative treatment,” said Burgess.
Charcot-Marie-Tooth type 2D patients carry dominant mutation in the Glycyl tRNA-Synthetase gene (GARS), but Caroline is the only person in the world that carries this specific DNA change in GARS. Caroline’s disease is an atypically severe form that includes early-onset motor neuropathy, leaving her wheelchair-bound. Burgess and colleagues engineered exactly the same mutation into mouse models and confirmed that it causes an early onset severe motor neuropathy in the mice, just like it does in human patients. In collaboration with Scott Harper, Ph.D., a principal investigator in the Center for Gene Therapy at the Research Institute at Nationwide Children’s Hospital in Columbus, Ohio, they developed a gene therapy specifically targeting the mutant gene to use in their mouse model of this disease.
“By delivering this gene therapy in mice, we were actually able to almost completely prevent the neuropathy from developing, and the treated mice actually were very difficult to tell from a normal healthy sibling mouse. This has been exciting,” said Burgess.
Next, the researchers are trying to pursue this gene therapy even further by working on a more general approach that they hope can fix any mutation in the GARS gene. In addition to these gene therapy approaches, the researchers are also looking at drug approaches to target a particular cell pathway in the disease. So far, they’ve tried one experimental drug in mice, which effectively treated them.
“Using these mice and through basic science approaches of gene expression analysis and understanding the mechanisms underlying the disease, we've actually identified another therapeutic strategy that was previously completely unknown for these diseases,” said Burgess. He and his collaborators are currently talking with pharmaceutical companies about how to develop the drug into a treatment and a trial for this class of Charcot-Marie-Tooth disease.
From hope to reality
Lutz researches mice as a model for human neurodegenerative disease, with an emphasis on best practices for research and preclinical drug testing. She emphasized that rare diseases are actually not so rare, and that they have important implications for more common disorders: “With over 7,000 different rare diseases identified to date, the impact is really in the millions on the population,” she said.
“The approach for the disease is important, not only for the families that are affected and the patients themselves, but also to give us a little bit more insight in how we can learn from our experience in rare diseases, to think about how we may approach more common diseases like Alzheimer's disease or diabetes.”
Lutz discussed her research into spinal muscular atrophy (SMA), a neuromuscular disease characterized by muscle weakness and atrophy that appears in one out of every 10,000 babies born. Using mouse models, her research provided the essential foundation of knowledge of the mechanisms of SMA and , the first FDA-approved drug to treat children (even newborns) and adults with SMA.
“This was one of the first therapeutic strategies that had demonstrated success, and the news keeps on getting better,” said Lutz. She shared that since 2016, gene therapy has also been approved by the FDA as a treatment for SMA, as has a drug from Roche Pharmaceuticals.
“Not only do we have efficacious therapeutics, but we have delivery mechanisms with greater biodistribution, greater availability and ones that can be taken orally at home,” she explained.
She concluded by sharing the story of Chance, a child who was born with SMA after his sister died from the disease at seven months of age. When Chance was born, his parents decided to give him the therapeutic. Today, Chance is a very healthy child with no signs of developmental delay or neuromuscular disease in his future. “Again, one of the very promising success stories, one that we think could be a tremendous blueprint moving forward for many other diseases,” said Lutz.
“At the beginning, 30 years ago, we spent a long time trying to figure out which genes are involved in disease,” said Liu. “The aspiration for gene therapy was simply an idea and a hope. Now, as you can see, it will be a reality.”