Led by neurologist Dr. Juan-Sanchez-Ramos, the mouse-model study will refine a noninvasive nose-to-brain delivery system using manganese nanoparticles
Huntington’s disease (HD) is an incurable, hereditary brain disorder that typically strikes adults in the prime of their lives – gradually affecting movement, mood and mental activity. Involuntary “dance-like” movements, known as chorea, are the most common motor symptoms. Patients also commonly develop depression and suicidal thoughts, and increasing difficulty with cognitive function makes it difficult to hold a job.
The one drug currently approved by the Food and Drug Administration to alleviate chorea does not change the course of HD.
When the single lethal gene for HD was discovered in 1993, USF Health neurologist Juan-Sanchez, MD, PhD, promised some patients he would help find a cure or effective treatment for the rare, but ravaging, disease that runs in families. At the time, he was a clinical team member of the U.S.-Venezuela Collaborative Research Project, a landmark study that identified and documented cases of HD and the disease’s progression in a unique community of families in Lake Maracaibo, Venezuela.
While celebrating the gene’s discovery with other clinicians in a village, he asked some HD patients gathered why they were not applauding the breakthrough. They answered with a typical Venezuelan gesture, “¿Y la cura?’” Dr. Sanchez-Ramos said. Translation: “So, where’s the cure?”
The pledge he made early in his career got a major boost last month when USF Health was awarded a new five-year, $2.3 million grant from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke. Principal investigator Dr. Sanchez-Ramos and his team — using a mouse model for Huntington’s disease — will assess and refine a new nanoparticle carrier system they’ve designed to transport therapeutic gene-silencing molecules from the nasal passages to the brain. The interdisciplinary team includes researchers from the USF Department of Neurology, USF Nanomedicine Research Center, Moffitt Cancer Center and the University of Massachusetts Medical School’s RNA Therapeutics Institute.
“This NIH study will allow us to test exactly how the nanoparticles get from the nose to the brain, how they are disseminated from the olfactory bulb to other parts of the brain, and how long they stay before dissipating,” said Dr. Sanchez-Ramos, professor of neurology and director of the Huntington’s Disease Center of Excellence at the USF Health Morsani College of Medicine.
“We want all parts of the brain to be exposed to these gene silencing molecules, because Huntington’s is a global brain disease; as the disease advances, no part of the brain is spared”.
There is still much work to be done but, if proven successful, the nose-to-brain approach could be used to non-invasively (via nasal spray or drops) deliver all kinds of drugs, including DNA therapy and nerve growth factors, which would otherwise be blocked from entering the brain by the blood-brain barrier.
“It could have applications for modifying a wide range of brain disorders,” Dr. Sanchez-Ramos said.
Gene-Silencing Technology Without Neurosurgery
The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop HD have an excessive number of these consecutive C-A-G triplet repeats — greater than 39. The defective gene leads to a toxic huntingtin protein, which appears to play a critical role in nerve cell function. HD is autosomal dominant, meaning if one parent has a copy of the faulty gene each child’s chance of inheriting the disease is 50 percent. The disease emerges slowly, usually between ages 30 and 50 (average age of diagnosis in the United States is 38), but onset can be earlier or later. Research suggests that the greater the number of C-A-G repeats the earlier symptoms tend to appear and the faster they progress.
Gene therapy is not new to HD or other neurodegenerative diseases. In the past, Dr. Sanchez-Ramos said, it primarily involved replacing a missing gene or delivering therapeutic molecules to help enhance cell survival. More recently, research applications using small interfering RNA, or siRNA, continue to advance gene therapy’s potential use to modulate the expression of genes, including silencing or suppressing overactive genes.
“Researchers have already found that you can silence the Huntington’s disease gene in animal models,” Dr. Sanchez-Ramos said, “but no one has yet delivered these gene-silencing molecules other than surgically — either by stereotaxic injection of viral vectors, or by direct infusion into the brain or cerebrospinal fluid.
“The neurosurgical approach is just not feasible for patients with a chronic illness that gradually encompasses the entire central nervous system.”
Source: University of South Florida