University of South Florida

USF gets $2.3M NIH grant to test new Huntington’s disease therapy merging nanomedicine and gene silencing (Audio)

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.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Dr. Juan Sanchez-Ramos, professor of neurology at the USF Health Morsani College of Medicine, is the lead investigator for a new $2.3-million NIH grant studying a non-invasive drug delivery system designed to safely and effectively transport large therapeutic molecules (nucleic acids) from nose to brain.

COPH sound-icon-png Listen to Dr. Sanchez-Ramos talk about a major obstacle to gene therapy.

Where’s the cure?

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.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

From left, the USF team of investigators includes Gary Martinez, PhD (Moffitt Cancer Center); Dr. Sanchez-Ramos; Vasyl Sava, PhD; Xiaoyuan Kong; Subhra Mohapatra, PhD; Shijiie Song, MD; and Shyam Mohapatra, PhD. Not pictured are Neil Aronin, MD, and Anastasia Khvorova, PhD, both of the University of Massachusetts RNA Therapeutics Institute.

COPH sound-icon-png Dr. Sanchez-Ramos comments on the nose-to-brain nanocarrier delivery system his team will be studying and refining.

Delivering therapeutic molecules for a global brain disease

“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.”

Overcoming a major obstacle: the blood-brain barrier 

Preliminary mouse model experiments indicate the unique nanocarrier system designed by the USF researchers will overcome the major obstacle of invasive delivery as well as bypass the blood-brain barrier, a gatekeeper between the blood and brain tissue that selectively filters which molecules can enter the brain.

USF has patent pending for the system, which incorporates manganese-containing nanoparticles that rapidly target brain tissue after simple nasal administration.  The biodegradable nanoparticles encapsulate gene-silencing molecules made to inhibit the activity of the HD gene.

“The system transports the nanoparticles from nose to brain where siRNA (the gene-silencing molecule) is released and triggers the dissolving of messenger RNA so that it cannot go on to produce the abnormal protein that causes Huntington’s disease,” Dr. Sanchez-Ramos said.  “Our approach is promising, reasonable and safe.”

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Dr. Sanchez-Ramos directs the Huntington’s Disease Society of America Center of Excellence at USF, where he cares for patients, many of whom are enrolled in clinical trials offered through the center. Kristy Yehle, right, participates in Enroll-HD, an international observational study for Huntington’s disease families.

In their series of NIH-supported studies, the USF researchers will visualize and track nose-to-brain transport of the manganese-containing nanoparticles in the mice using magnetic resonance imaging. (The contrast agent safely injected into patients undergoing some MRI tests contains manganese.)

Dr. Sanchez suspects that the nanoparticles may access the deeper regions of the brain through spaces surrounding the brain’s neurons and blood vessels rather than by the olfactory nerves alone, but the experiments will help quantify how the nanocarrier system works.  The study will also evaluate the effectiveness of the gene-silencing molecules in reducing or preventing motor and behavioral symptoms in the HD mice and look for ways to optimize the distribution and dosing.

On the threshold of a cure

The Huntington’s Disease Society of America (HDSA) Center of Excellence at USF, one of the largest regional referral centers in the Southeast, has treated more than 600 patients and their families since earning the HDSA designation more than 10 years ago. Many patients enroll in clinical studies testing investigational drugs and tracking the natural history of the disease in search of biomarkers.

Dr. Sanchez-Ramos' team was awarded 2.3 million dollar grant

Early in his career, while working as part of an international research team in Venezuela, Dr. Sanchez-Ramos promised some patients he would help find a cure or effective treatment for Hurtington’s disease.

At USF’s center, Dr. Sanchez-Ramos listens to their stories about struggling with and overcoming the challenges of living with HD and their determination to live each day to the fullest. The clinician-scientist remembers the promise he made in Venezuela.  He remains optimistic that research by USF and others combining nanomedicine and gene-silencing technology will lead to human trials, and ultimately, effective therapies to prevent HD or delay its progression.

“We’ve found a way to hit this single-gene disease with global symptoms at its source – by knocking out the abnormal gene expression,” Dr. Sanchez-Ramos said.

“I’m more hopeful than ever that we’re on the threshold of a cure for Huntington’s disease.”

Photos by Eric Younghans and animated graphic by Sandra Roa, USF Health Communications and Marketing



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