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Researcher Highlight: Dr. Timothy Miller
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October 3, 2012
Timothy Miller, MD, PhD, serves as Assistant Professor of Neurology at Washington University in St. Louis; Faculty Member of the Hope Center for Neurological Disorders; and Director of the Christopher Wells Hobler Laboratory for ALS Research
Timothy Miller’s, MD, PhD interest in exploring neurodegenerative disease began as a graduate student studying the basic mechanisms of cell death. During his residency and fellowship under the direction and guidance of the well-known late Dr. Richard K. Olney at the University of California at San Francisco, Dr. Miller’s passion for investigating neuromuscular disorders evolved. His experiences in Dr. Olney’s clinic started him on a path towards learning more about familial ALS (FALS). Much of his research has focused on “turning off” harmful genes, specifically SOD-1, in the brain and spinal cord of patients with FALS.
Dr. Miller’s previous research in conjunction with Isis Pharmaceuticals, Don Cleveland, PhD, (University of California at San Diego), and Richard Smith, MD, (Center for Neurologic Study) has led to a recent clinical trial using the concept of “turning off” SOD1 in patients with FALS. Along with Merit Cudkowicz, MD, MSc, (NEALS Co-Chair and Neurology Chief at Massachusetts General Hospital), Dr. Miller served as the Principal Investigator for the Phase I ISIS trial, which has demonstrated favorable safety results. However, what exactly is the thought process behind “turning off” SOD-1?
The process can be thought of much like removing a broken part of a house. Dr. Miller explains, “DNA is the blueprint and RNA is its translation, much like written instructions. RNA in turn makes protein, the building blocks of the human body. If you’re building a house, it would be the brick, the mortar, the pipes, the electrical work.” A mutation, or mistake, in that DNA blueprint can lead to a set of RNA instructions that makes an abnormal protein. Sometimes that one abnormal brick, mortar, or pipe is enough to bring the whole house down. “Proteins are elaborately folded structures,” he continues. “Think of origami folding paper to make a paper crane. If your set of instructions has a mistake, you have something more akin to a paper wad, rather than a beautifully folded structure.” That misfolded protein, the wad, can cause enormous problems over time, which is the case with SOD1 Familial ALS Dr. Miller and his team have developed a way to delete a small part of RNA, which then no longer makes this abnormal, or misfolded, protein. Supported by the Muscular Dystrophy Association, the ALS Association, and Isis Pharmaceuticals, the Isis trial is the first of its kind, in which researchers have taken technology called an antisense oligonucleotide (ISIS 333611) and delivered it directly to the cerebrospinal fluid (CSF) of FALS patients. Results indicated that ISIS 333611 was well-tolerated and that there were no safety concerns. Dr. Miller adds that the pharmacokinetics, or the levels of a drug in the body and the speed at which the body metabolizes and eliminates a drug, were on target with his team’s prediction. Understanding pharmacokinetics allows them to improve their understanding of infusions directly into the spinal fluid as a delivery method to treat patients with FALS.
These Phase I results display the importance of further investigation of antisense oligonucleotide as a therapeutic candidate for FALS. “We are very enthusiastic about moving forward in treating SOD1 related ALS.” Despite antisense oligonucleotide technology being a relatively new approach to treating neurodegenerative diseases, it “offers great promise for a way to directly focus in on and target the known problem; it allows us to be on target with the mechanism of the disease. (However,) I would acknowledge that we are still at an early stage; we need to continue to move forward,” says Dr. Miller. The technology has the potential to have positive implications beyond the scope of Dr. Miller’s current research. “There has been a lot of interest in C9ORF72 (a recently identified ALS gene) and I think it is very likely, even though the data is still emerging, that we could use a similar antisense oligonucleotide approach to decrease harmful expression in the C9ORF72 gene.”
Additionally, Dr. Miller has other ongoing studies that can inform the next SOD-1 interventional clinical trial, which he and his collaborators are actively working to bring forward. In the research pipeline is a natural history of SOD1 study with the goal of understanding the disease course. They are also investigating the half-life of SOD-1 in CSF; one of the major components of the next SOD-1 antisense clinical trial will be to investigate whether there is a pharmacodynamic effect. That is, does the drug designed to lower SOD-1 in CSF actually do what it is intended to do? “We have recent data that we have generated that we think shows that SOD-1 will be an excellent pharmacodynamic marker to show whether the drug is working or not in the central nervous system. Part of understanding when to sample the CSF will be understanding the half-life of SOD-1 in the CSF,” says Dr. Miller.
No matter what project Dr. Miller discusses, he stresses the importance of the research “team.”
With each challenge, it is the efforts and collaboration of scientists with the same goals that make each challenge worth undertaking. Moreover, it is the ALS patients who are Dr. Miller’s inspiration. “People who have urged me to move as quickly as possible…who have reminded me that finding treatments for them is terribly urgent…patients who need us to come up with new therapies that worked yesterday.” It is Dr. Miller’s hope that, as a group, ALS researchers will come up with effective new therapies to improve outcomes for PALS and ultimately eradicate the disease.
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