The DNA of someone with a chronic neurological disease has the potential to reveal a lot about their diagnosis and how it can be treated. A team from the academic and clinical arms of Northwestern Medicine has been assembled with the purpose of studying the DNA of certain patients with these diseases and pinpointing specific genetic mutations or phenotypes that may be present. Everything from genetic canvassing to generating disease models to creating therapeutic compounds is happening in-house at Northwestern, a unique model in the rapidly expanding field of personalized neurology.
“You need a lot of people to execute this cycle: clinicians, geneticists, stem cell experts, medicinal chemists and clinical trial experts,” said Dimitri Krainc, MD, PhD, chair of the Ken & Ruth Davee Department of Neurology and director of the Center for Neurogenetics. “But it’s all based on genetics, so we start with patient samples and genetic screening.”
Currently, Northwestern experts are focused on subpopulations of patients with Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and epilepsy. Creating targeted genetic therapies for these neurological diseases begins with geneticists who analyze patient genomes, looking for mutations that could cause or modify disease. Next, scientists generate induced pluripotent stem cells that differentiate into neurons, mimicking the diseased neurons in the brain of a patient with Parkinson’s disease, for example.
The scientists use these models to identify therapeutic pathways, handing those pathways over to medicinal chemists who develop compounds to treat the disease. Once therapies are created, they are tested in clinical trials, often in partnership with private companies.
Krainc is on the front line of personalized neurology, and his lab has a number of high-profile projects, including a recent study published in the journal Science.
“Every patient is different, so treating neurological disease isn’t one size fits all,” said Krainc, also the Aaron Montgomery Ward Professor of Neurology in the Division of Movement Disorders and of Neurological Surgery and of Physiology. “There are different reasons why people develop disease, so we try to address that in a targeted manner.”
Bedside to Bench, Parkinson’s and Epilepsy
Obtaining genetic data for Parkinson’s disease requires tight integration with the Northwestern University Parkinson’s Disease and Movement Disorders Center (NUPDMDC), led by Tanya Simuni, MD, the Arthur C. Nielsen, Jr., Research Professor of Neurology in the Division of Movement Disorders.
At the newly established neurogenetics clinic, and its associated collaboration between clinicians and scientists, cases that may have a genetic component are brought to the attention of geneticists such as Steven Lubbe, PhD, assistant professor of Neurology in the Division of Movement Disorders and a member of the Center for Genetic Medicine.
“If we find a candidate variant in a patient, through the NUPDMDC biorepository, we then look for that variant in family members,” Lubbe said. “If that variant is only seen in individuals with the disease, and not in family members without it, it represents the start of an exciting journey where we try to understand the underlying molecular biology of disease using neurons derived from patient skin cells. The hope here is that if we know what damage the change does in the patient’s own neurons, we may be able to develop a novel target that can be returned to the patient for a more personalized approach to disease intervention and management.”
Lubbe is also using the same approach to identify modifiers of Parkinson’s disease.
“When it comes to certain mutations, not everyone who has them gets Parkinson’s, so we’re using genetic information from affected and unaffected family members with the same change to help find these modifiers and study them in their own neurons,” Lubbe said.
A therapeutic compound for Parkinson’s disease developed at Feinberg is currently undergoing clinical trials and the Department of Neurology will be expanding its focus to include Alzheimer’s disease in the near future, demonstrating the productivity of this approach even in early stages.
Genetic data collection of epilepsy patients, similar to Parkinson’s, is driven by the relationship between the research enterprise and a patient clinic at Northwestern Medicine. A desire to integrate genetics into clinical care has led clinicians to be more active in sharing interesting cases and genetic data, according to Gemma Carvill, PhD, assistant professor of Neurology and of Pharmacology.
“Neurologists who treat adults weren’t thinking as much about genetics seven or eight years ago,” Carvill said. “Now, we have clinical epileptologists who are very interested in genetics and asking patients about family history, which is not something that had necessarily happened in adult neurology before.”
This heightened awareness has led to a surge in identifying genes connected to epilepsy, ballooning from about five genes to more than 80 genes during the last decade.
“Most of the science revolves around ion channels and neurotransmitters; in the past we thought these were the main pathways affected in epilepsy, but that’s not everything,” Carvill said. “It turns out there is this whole other class of genes that influence how the brain is made and functions that we can study for connections to epilepsy. We’re interested in the proteins that instruct the development of the brain and use stem cells to model epilepsy in the dish.”
While identifying genes is beneficial, it only has real impact when it’s integrated into therapies or clinical care, which is an important consideration, Carvill said.
“We want to take that next step and find out how we can capitalize on these discoveries and new biological pathways to understand epilepsy and find new treatments,” she said. “The genetics and and epilepsy communities have spent a lot of time thinking about how to approach these questions.”
A Team in Place
New faculty with expertise in translational neurogenetics have been recruited to the Department of Neurology over the past four years to help execute the translational program in neurogenetics, under the umbrella of the Center for Neurogenetics. This includes Lubbe and Carvill, as well as Niccolo Mencacci, MD, PhD; Evangelos Kiskinis, PhD; Joseph Mazzulli, PhD; Jeffrey Savas, PhD; Robert Kalb, MD; Gabriela Caraveo Piso, PhD, and Jianbin Zheng, PhD.
The new faculty are essential to providing the scientific framework needed to turn genetic discoveries into patient treatments.
“This is pretty unique, not too many places are doing it like this,” Krainc said. “This is extremely important for the future of neurology.”
-Will Doss, Northwestern Medicine Feinberg School of Medicine
This article originally appeared in the December 2017 edition of the Breakthroughs newsletter.