School of Medicine

Antisense Drugs for Huntington’s, ALS and Prion Diseases Could Meet the Dire Need for Brain Treatments

Among the human body’s many maladies, few have stumped medical researchers like those that decimate the brain. After decades of effort, effectively treating—let alone curing—neurodegenerative disorders such as Huntington’s and Alzheimer’s disease has been a source of frustration for many, as old theories are questioned and clinical trials fail.

Basic scientists have achieved some progress. Over the past few decades, they have made serious headway in identifying single inherited genes responsible for genetic forms of various neurodegenerative diseases such as Alzheimer’s—and also the molecular and neural mechanisms behind nongenetic, or sporadic, forms of brain maladies. Yet translating these findings into working therapies has proved challenging.

With genetic engineering technologies, such as CRISPR, that literally rewrite our DNA still a ways away from routine use, a number of clinical researchers have turned to a more immediate genome-based approach to treat disorders of the brain: manipulating RNA to modify levels of proteins associated with disease…

…So many neurological and neuromuscular diseases result from either having too much or too little of a particular protein, and theoretically, antisense therapy could intervene to restore normal protein function. Let us say a patient’s brain is overrun with too much amyloid protein, a key characteristic of Alzheimer’s disease pathology: Getting enough of an ASO to bind to the RNA that produces the protein could bring its levels down—to normal in a perfect world. Another protein called tau also builds up in the brains of patients with Alzheimer’s or other tau disorders, such as the chronic traumatic encephalopathy experienced by athletes and soldiers. The list of these pathological proteins also includes alpha-synuclein in Parkinson’s, huntingtin in Huntington’s and SOD1 in some forms of ALS.

“There is so much to be excited about in the antisense oligonucleotide realm,” says Washington University in St. Louis neurologist Timothy Miller. “Just within the past few years, there’s been an incredible amount of activity.”

Miller has studied ASOs for years. He did pivotal research in lab animals that showed these molecules dispersing widely throughout the brain—studies he characterizes as an “entry point for using this technology in neurologic disease.” Miller’s work has served as the basis for an ongoing phase I trial in Europe. His own group has partnered with Ionis Pharmaceuticals and Biogen to test the approach in ALS. That research has so far shown that an ASO that binds to SOD1 is not only safe but lowers levels of the protein in patients’ cerebrospinal fluid by 37 percent. Miller presented the data at the American Academy of Neurology’s annual meeting this past May.

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