The academic medical center is applying cutting-edge science with the hope of reducing or eliminating the cause of PKU, the most common inborn error of metabolism

USF Health Genetics and Metabolism and Tampa General Hospital (TGH) have teamed up to deliver one of the world’s first investigational gene therapies for the rare inherited disease phenylketonuria (PKU) as part of a pivotal multisite clinical trial.

USF Health is one of four sites – three in the U.S. and one in the United Kingdom – currently participating in a phase 1/2, open-label clinical trial testing the safety and effectiveness of an adenovirus vector-mediated gene therapy for PKU. The study expects to enroll up to 100 patients ages 15 and older. Many PKU patients struggle to stick to a strict low-protein diet needed to control harmful levels of the amino acid phenylalanine (Phe), which is not metabolized in people with PKU.

“While rare, PKU is the most common inborn error of metabolism. So, it’s kind of mind-blowing to me that we could be on the verge of potentially offering a cure to patients with a critical enzyme deficiency identified at birth,” said site principal investigator Amarilis Sanchez-Valle, MD, an associate professor of pediatrics at the USF Health Morsani College of Medicine, who treats children and adults with metabolic disorders. “There are questions yet to be answered, but we’re hopeful about the prospects for a one-and-done gene therapy approach that may (permanently) fix PKU.”

The first patient intravenously administered the investigational gene therapy (called BMN 307) at Tampa General in early May was the second PKU patient in the U.S. to receive the treatment as part of the multicenter trial, Dr. Sanchez-Valle said. The USF Health Metabolic Genetics Clinic has identified several more potentially eligible patients for this trial.

Babies born with PKU have defects in a metabolic gene that makes the enzyme phenylalanine hydroxylase (PAH). This PAH enzyme is needed to break down Phe, an amino acid in all protein-containing foods, including chicken, meat, eggs, dairy, nuts, grains, and legumes. Left untreated, high or unstable levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychological complications, affecting the way a person thinks, feels, and acts. The lifelong condition is controlled primarily by eating a very restrictive, low-protein diet that is difficult to maintain.

Principal investigator Amarilis Sanchez-Valle, MD, associate professor of pediatrics at USF Health, treats children and adults with metabolic disorders, including PKU.

Dr. Sanchez-Valle and the other trial investigators will assess the BMN 307 gene therapy’s ability to work well without diminishing over time. They will monitor study participants enrolled in the trial for five years, evaluating whether a single dose of the gene therapy can restore natural Phe metabolism, normalize Phe levels in the blood, and enable patients with PKU to eat normally.

Two drugs are approved in the U.S. to help treat PKU. Kuvan, a PAH enzyme activator, gives a small percentage of patients slightly more flexibility in their diet. The injectable enzyme substitution Palynziq, available for adults only, is the first allowing patients to eat a normal diet. However, the drug carries a warning about the possibility of severe immune reactions, and some patients are averse to giving themselves daily injections and risking side effects.

The gene therapy uses an adeno-associated viral vector (virus engineered to be harmless) to shuttle a fully functional copy of the PAH enzyme gene into the liver cells where Phe is broken down. Once the vector infects the liver cells, the cells read the code from the normal gene and begin naturally reproducing the missing or deficient PAH enzyme.

Preclinical studies of BMN 307, which included years of dosing, safety and other data collected in laboratory models, were promising, Dr. Sanchez Valle said. “Hopefully, this experimental gene therapy will provide a biochemical cure. But it’s important to emphasize that we are not changing the patient’s DNA. Their genome remains the same, because the vector does not target and deliver the working gene to every cell in the body.”

The USF Health-TGH multidisciplinary team implementing this gene therapy clinical study includes the regulatory staff and study coordinators who make the trial possible, the hospital pharmacists who painstakingly prepare the IV suspension containing the gene-carrying vector, and TGH hematology-oncology nurses with expertise in drug side effects.

The same day the team administered their first PKU gene therapy, Dr. Sanchez-Valle visited the neonatal intensive care unit to check on a newborn diagnosed with PKU. (Because PKU symptoms can be so serious, the U.S. and many other countries screen infants at birth to ensure early diagnosis and treatment to avoid intellectual disability and other complications.) The infant’s mother had two other children with PKU. Babies with the metabolic disorder typically cannot be breastfed because controlling protein-rich milk intake, and therefore high or unstable Phe levels, poses a significant challenge.

“Just think if sometime within the next few years we could potentially provide that mother’s children with one infusion so they would not need to follow an extremely restrictive diet. It would also give new mothers like her the opportunity to nurse their babies without anxiety about PKU interfering,” Dr. Sanchez-Valle said.

People with the inherited metabolic disorder PKU must strictly avoid protein-rich foods to control harmful levels of the amino acid phenylalanine (Phe).

Advances in technology have opened new ways of delivering targeted gene therapies, including creating other vectors to deliver therapeutic genes, like lentiviruses and lipid nanoparticles, as well as possibly fixing PAH mutations with gene editing tools such as CRISPR.

“Our team is starting with PKU, but we believe down the line gene therapy may offer more options for patients with other rare diseases,” Dr. Sanchez-Valle said. “We’re excited about applying cutting-edge science that helps make (medical) history.”

USF Health preclinical study tests several formulations of chitosan-enriched siRNA nanoparticles intended to improve gene therapy targeting neurodegenerative diseases

Neurologist Juan Sanchez-Ramos, MD, PhD, director of USF Health’s HDSA Huntington’s Disease Center of Excellence, examines patient and clinical trial participant Brittany Bosson.

Huntington’s disease (HD) is a hereditary brain disease that typically strikes adults in the prime of life – leading to progressive deterioration of movement, mood and thinking. While some drugs temporarily alleviate symptoms, currently no therapies prevent, slow or stop the course of HD.

Juan Sanchez-Ramos, MD, PhD, the Helen Ellis Professor of Neurology and director of  the HDSA Huntington’s Disease Center of Excellence, University of South Florida Health (USF Health), sees firsthand how this devastating illness – sometimes described as a mix of Parkinson’s disease, ALS and Alzheimer’s disease — affects patients and their families.  For the last several years, even as he leads clinical trials evaluating potential new drugs, the physician-scientist has worked with a mouse model of HD to develop and test a nanoparticle system that can precisely deliver gene therapy from the nose to areas of the brain most affected by HD.

He is closer than ever before to a viable noninvasive treatment – one that could be administered by nasal spray or drops, rather than spinal puncture or direct injection into the brain.

In a preclinical study published Oct. 27 in Nanomedicine: Nanotechnology, Biology and Medicine, senior author Dr. Sanchez-Ramos and colleagues build on their earlier findings demonstrating that chitosan-enriched, manganese-coated nanoparticles loaded with small interfering RNA (siRNA) could be successfully delivered by nose drops to targeted parts of the brain affected by HD.  In a Huntington’s disease mouse model the nanoparticles reduced expression of the mutated HTT gene that causes HD by at least 50% in four regions: the olfactory bulb, striatum, hippocampus and cortex. The defective HTT gene leads to production of a toxic form of protein, known as the huntingtin protein. In essence, this new treatment silences the genetic message “telling” a cell to generate more huntingtin proteins. To ultimately benefit patients, the abnormal protein production must be reduced enough to block or slow the dysfunction and eventual loss of nerve cells accounting for clinical symptoms.

“Our nose-to-brain approach for delivery of gene therapies is non-invasive, safe and effective,” said Dr. Sanchez-Ramos, a co-inventor of the novel anti-HTT siRNA nanoparticle delivery system patented by USF.

Searching for ways to optimize HD gene silencing

For the latest study, reported in Nanomedicine, Dr. Sanchez-Ramos collaborated with researchers from the USF Health Department of Neurology and the University of Massachusetts Medical School’s RNA Therapeutics Institute.  Seeking to optimize HD gene silencing when the siRNA is delivered by a nasal route, the team tested different formulations and sizes of the nanoparticles in a mouse model expressing the human HD gene. Among their findings:

— Four different versions of the nanoparticles tested lowered HD gene expression in the brain by 50%. However, lowering levels of the toxic huntingtin protein in brain tissue took longer, with the highest reduction of the protein (53%) seen in the olfactory bulb at the base of the brain and the lowest (38%) in the cerebral cortex, the brain’s outer layer. Also, simply administering “naked” siRNA through the nose (without the protective chitosan encasement) did little to reduce HD gene expression even though previous research has shown similar naked siRNA injected directly into the brain was highly effective.

— Enclosing the siRNA in chitosan protected the silencing RNA from being prematurely degraded “en route” to its HD brain targets. The compound chitosan is derived from the hard outer skeleton of shellfish or the external skeleton of insects. Encapsulating siRNA into a chitosan nanoparticle allowed the silencing RNA to be enriched to higher doses without damaging the molecule, resulting in significant reduction in HD gene expression, the researchers report.

— Increasing the number siRNA nanoparticles within a defined dose of nose drops is a key to improving therapeutic potential. “The ability to fabricate concentrated NP (nanoparticle) preparations without damaging siRNA content is a critical factor for successful intranasal delivery of gene silencing agents,” the researchers concluded.

A major challenge of gene therapy for HD and other neurodegenerative diseases has been getting the molecules intended to replace a missing gene or suppress an overactive gene past the blood-brain barrier, a kind of defensive wall that selectively filters which molecules can enter the brain from circulating blood.

But over the last several years, research progressed in overcoming this barrier and promising laboratory findings set the stage for clinical trials in patients with HD.

For example, led by Dr. Sanchez-Ramos, USF Health is the only Florida site participating in the Roche-sponsored GENERATION HD1 Study. This pivotal phase 3 international clinical trial is testing whether a huntingtin-lowering, antisense oligonucleotide drug can halt underlying pathology of the disease enough to improve symptoms in adult patients. The injectable drug, administered directly into the cerebral-spinal fluid, successfully bypasses the blood-brain barrier and stopped disease progression in laboratory models. However, the investigational drug must be administered every two months by lumbar puncture at the clinic.

The normal huntingtin gene contains a DNA alphabet that repeats the letters C-A-G as many as 26 times, but people who develop Huntington’s disease have an excessive number of these consecutive C-A-G triplet repeats — greater than 39.| Graphic by Sandra C. Roa

Working toward a simpler, noninvasive treatment

With a chronic illness that gradually encompasses the entire central nervous system, like HD, even minimally-invasive injections with fine needles or infusions may pose risks of infection or other complications associated with neurosurgical procedures, Dr. Sanchez-Ramos said. So, he continues to work toward a noninvasive nose-to-brain treatment that would be simpler to repeat and well-tolerated by patients over their lifetime.

Dr. Sanchez-Ramos says the idea for incorporating nontoxic amounts of manganese chelate into the chitosan-based nanoparticles to help gene therapy delivery was sparked by early studies investigating how welders exposed to high levels of neurotoxic manganese oxide from welding fumes developed Parkinson’s disease symptoms.  It turns out that the olfactory nerve has an affinity for the chemical manganese.

“Manganese is good at guiding our nanoparticles from the nasal passages to the olfactory nerves and transporting the particles directly to structures deep in the brain… Realizing that was one of our biggest breakthroughs,” he said.  Manganese also permits the nanoparticles to be visualized by MRI imaging, so that their distribution and accumulation in different regions of brain can be tracked.

The nose-to-brain method of delivering the manganese-containing siRNA nanoparticles needs to be tested in a larger-brain animal model before moving to human trials.

The USF Health study was supported by a grant from the National Institute of Health’s National Institute of Neurological Disorders and Stroke.

As his preclinical research on nose-to-brain delivery of gene therapy for Huntington’s disease progresses, Dr. Sanchez-Ramos serves as Florida principal investigator for a worldwide clinical trial testing an injectable drug designed to slow the progression of Huntington’s disease.

-Photos by Allison Long, USF Health Communications and Marketing

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The age of human gene therapy has at last begun in earnest. This new era presents both tremendous opportunities and hope for our patients, but also brings unprecedented challenges, as accelerated discoveries and expensive new treatments are creating new clinical, political and ethical challenges.

I’ll share some USF Health research efforts to advance gene therapy for neurological diseases – but, first, some context.

Following the discovery of the structure of DNA in the 1950s, medical researchers predicted we would soon decipher the molecular mechanisms of hereditary diseases, enabling us to then genetically engineer treatments for those disorders shortly thereafter.  Although progress over the next several decades was far slower than anticipated, the launch of the Human Genome Project in 1990 made that future seem imminent.

However, in the late 1990s, the tragic death of a young patient volunteer (due to a systemic reaction to an adenovirus vector), along with a series of technical and clinical trial failures made effective gene therapy again seem like a distant dream.  Nevertheless, progress resumed in the mid-2000s and technological advances finally translated into effective clinical treatments over the ensuing decade.

In 2018, the FDA issued its first approval for a true in vivo gene therapy of a hereditary disorder (hereditary retinal dystrophy), and another for hereditary transthyretin amyloidosis, both of which are devastating diseases with no truly effective previous treatments.  These approvals were quickly followed by several more, including treatments and a possible cure for hereditary spinal muscular atrophy (SMA), a progressive and fatal paralyzing disease of infants and children.

Over the last year, a host of new therapies entered the pipeline for testing and FDA consideration. Many have shown robust and often dramatic Phase 2 and 3 evidence of efficacy.

Several USF Health Morsani College of Medicine (MCOM) researchers are on the front lines of these studies:

• Juan Sanchez-Ramos, MD, PhD, director of the USF Health Huntington’s Disease (HD) Center, received a $2 million NIH grant to develop and test a smart nanoparticle delivery system for placing gene therapies more precisely (and noninvasively) into areas of the brain affected by HD. He is also now launching an antisense oligonucleotide gene therapy study in HD patients. HD results from a triplicate repeat gene mutation, which mutates the huntingtin protein into a toxic form; this new therapy blocks production of the mutant protein, slowing or even arresting the disease.
• Theresa Zesiewicz, MD, director of the USF Health Ataxia Research Center, is working with a group of industry partners to develop gene therapy strategies for Friedreich’s ataxia (another triplicate repeat disorder).
• Tuan Vu, MD, director of the USF Health ALS Center, is exploring potential human studies of a gene therapy for one of the most common forms of hereditary amyotrophic lateral sclerosis (SOD1 ALS), in collaboration with the company that just secured FDA approval for its SMA gene therapy.
• Bob Hauser, MD, director of the USF Health Center for Parkinson Disease (PD) and Movement Disorders, is collaborating with a pharma company on genetic modulation of the production of alpha-synuclein (a pivotal protein in the pathogenesis of PD) in animal models, and to consider how this might be adapted as a therapy for human PD.

Many other outstanding MCOM translational and clinical researchers are now also entering this rapidly expanding arena.

With these advances and many more to come, this modern era of gene therapy continues to build excitement.  However, scientific progress has been so rapid that the world’s health systems are struggling to keep up with the integration and adoption of these new technologies. In particular, the cost of targeted gene therapies can impede their widespread use in clinical practice; pharmaceutical companies have priced many of these new therapies (some of which may actually be lifetime cures), at the multimillion dollar mark for each patient treated.

Beyond gene therapy, new genetic engineering technologies have profound implications for humankind. The world’s scientific, ethical and governmental bodies are now striving to quickly define where the boundaries of this technology should be, and grappling with when and how to discourage premature human experimentation in sensitive areas.

As controversy in other areas where science and politics intersect has demonstrated, surmounting these challenges together as a worldwide community may, in the end, be the ultimate hurdle to overcome as we enter the brave new world of gene therapy.

Clifton L. Gooch, MD
Professor and Chair, Department of Neurology
USF Health Morsani College of Medicine

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. 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.

 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.

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.

 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.

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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 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.

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

Hosted by FARA and the USF Ataxia Research Center, the annual scientific symposium emphasizes a patient-centered approach to research

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For the first time in its seven-year history, the Friedreich’s Ataxia Scientific Symposium brought together several pharmaceutical industry leaders to discuss preclinical and clinical studies.  The companies are all attacking Friedreich’s ataxia (FA) on different fronts with the same goal in mind:  to get the first treatment for the rare, but devastating, neuromuscular disease approved and on the market as soon as possible.

The Sept. 17 symposium, hosted by the Friedreich’s Ataxia Research Alliance (FARA) and the USF Ataxia Research Center, drew an audience totaling more than 500, both live at the USF Marshall Center Ballroom and viewing the event in real-time through Ustream’s CureFA channel.

The symposium featured a discussion by leading representatives of pharmaceutical and biotechnology companies working with FARA and academia to conduct new research attacking Friedreich’s ataxia on several fronts.

Representatives and supporters of FARA, the research community, and patient and their families – many whom attended FARA’s Energy Ball gala on Saturday evening, Sept. 19 — were welcomed by USF President Judy Genshaft.

The translational center of excellence at USF is “one of the most active in the world, testing potential new drugs for Friedreich’s ataxia,” President Genshaft said. “We are unstoppable in the fight for a cure for FA.”

In the last seven years, the staff of the USF Ataxia Research Center, focused on identifying and developing effective treatments for inherited ataxia disorders, has expanded to eight, including two clinicians, a fellow, nurses and research coordinators.  Center Director Theresa Zesiewicz, MD, professor of neurology, gave an overview of the center’s eight clinical trials — six active and two finishing up. USF, one of 10 sites in the international FARA Collaborative Clinical Research Network, is recruiting patients for two of the three trials presented by pharmaceutical industry leaders at the symposium. The USF center is also working with Agilis, one of the biopharmaceutical companies at the symposium, to develop their gene therapy protocol, expected to be submitted in 2016 to the Food and Drug Administration (FDA).

USF President Judy Genshaft welcomed attendees to the USF Tampa campus for the seventh annual scientific symposium “Understanding Energy for A Cure,” hosted by the Friedreich’s Ataxia Research Alliance and the USF Ataxia Research Center.

Friedreich’s ataxia is triggered by a single genetic defect that limits production of frataxin, a protein vital to the function of the energy-producing factories, or mitochondria, of the cell. This leads to a variety of symptoms including neurodegeneration that can cause muscle weakness and loss of coordination and balance, energy deprivation and fatigue, vision impairment, slurred speech, aggressive scoliosis, diabetes and life-shortening cardiac disease. Most young people diagnosed with Friedreich’s ataxia require a cane, walker or wheelchair by their teens or early 20s. There are currently no approved treatments.

FARA President Ron Bartek and Executive Director Jennifer Farmer spoke about the progress in Friedreich’s ataxia research worldwide and the value of the organization’s 2,600-member patient registry in bringing together all its stakeholders.

FARA’s Executive Director Jennifer Farmer and President Ron Bartek.

Featured speaker Sanjay Bidichandani, MBBS, PhD, the chair of pediatric medical genetics at the University of Oklahoma College of Medicine and member of the FARA Board of Directors, was part of the team that first identified the Friedreich’s ataxia gene in 1996.  Fueled by resources and partnerships cultivated by FARA, Dr. Bidichandani said, the understanding of the disease process advanced relatively quickly since that genetic discovery and has yielded robust expansion of investigational drugs in the treatment pipeline.

A panel moderated by Dr. Bidichandani featured representatives from four biotechnology and pharmaceutical companies conducting Friedreich’s ataxia research in collaboration with FARA and academia – Jeffrey Sherman, MD, executive vice president for research and development and chief medical officer, Horizon Pharma; Jodi Cook, PhD, vice president of operations, Agilis Biotherapeutics; Colin Myer, MD, chief medical officer, Reata Pharmaceuticals; and Robert De Jager, MD, chief medical officer, Retrotope. Their newly activated studies cover a range of therapeutic targets, including finding ways to boost frataxin production, improving mitochondrial function, reducing mitochondrial damage and oxidative stress, and delivering gene therapy.

Featured speaker Dr. Sanjay Bidichandani, a member of FARA’s Board of Directors, was part of the group that discovered the gene for Friedreich’s ataxia in 1996. He gave an overview of the tremendous progress in less than 20 years leading to a robust treatment pipeline.

“FARA has really galvanized the patient community, academia, industry and even regulators to develop better insights into this disease and how we can all work together,” said Horizon Pharma’s Dr. Sherman. “At the end of the day, they’ve really brought to the forefront the importance of patient centricity and the voice of the patient in clinical and basic science research.”

Horizon Pharma has repurposed a drug already approved by the U.S. Food and Drug Administration for use in treating two other rare genetic disorders, chronic granulomatous disease and severe malignant osteopetrosis. The company recently launched a Phase 3 randomized, double-blind, placebo-controlled trial to test the safety and effectiveness of Actimmune® (interferon gamma-1b) in improving neurological function in 90 Friedreich’s patients at four U.S. sites. Previous research indicated that Actimmune®, which mimics a protein made by the body to help prevent infection, increases frataxin levels to reduce nerve cell depletion and muscle atrophy.

The symposium brought together representatives and supporters of FARA and the research community with patients in their families.

Agilis focuses on engineering and delivering therapeutic DNA to replace the damaged frataxin gene. Preclinical studies are employing a safe virus to optimally deliver the corrective gene to key targets, allowing safe and effective long-term expression of the frataxin protein.

Earlier this year Reata began a Phase 2 randomized, placebo-controlled, double-blind trial testing the safety and effectiveness of various dose levels of the oral medication RTA 408 in treating Friedreich’s ataxia. Known as the MOXle study, the trial is enrolling patients at sites worldwide, including USF. Preclinical studies have shown that RTA 408 directly activates antioxidative pathways to improve mitochondrial function.

This month USF enrolled the first of 18 patients in Retrotope’s 28-day randomized, double-blind controlled trial evaluating the safety of the investigational oral drug RT001 in ambulatory patients with Friedreich’s ataxia. USF and the University of California Los Angeles will be the only two sites for the Phase 1 study. The compound RT001 is a stabilized fatty acid shown to shut down the toxic free radical degradation of polyunsaturated fats, an essential component of cell membranes, and reduces further damage to the mitochondria.

Jade Perry, a member of the patient panel, was accompanied by her service dog Bo, a labradoodle.

The scientific panel was followed by a question-and-answer session on patients’ perspectives of living with Friedreich’s ataxia.  The panel was moderated by symposium host Clifton Gooch, MD, professor and chair of the Department of Neurology at the USF Health Morsani College of Medicine.

The four patient participants, all diagnosed in their teens or early 20s, emphasized a common theme – that they choose every day to carry on and live life to its fullest  despite the challenges of Friedreich’s ataxia.

Jade Perry, 25, was accompanied to the stage by the service dog she trained, a labradoodle named Bo.   Perry, who is finishing up a master’s degree in education from Coastal Carolina University, recently got her first full-time teaching job.

“I love riding my trike and try to keep my schedule packed so FA can’t slow me down,” she said.

Kendall Harvey, center, was diagnosed with later-stage Friedreich’s ataxia three years ago at age 25. “In spite of my diagnosis, my family and I are living life to the fullest,” she said.

Kendall Harvey, 28, diagnosed at age 25 with later-onset Friedreich’s ataxia, still walks unassisted.  She and her husband live in Austin, TX, with their 11-month old son Brooks.

Harvey, who participated in volleyball, track and other sports as a youth, said she noticed problems with agility and balance while taking dance lessons in preparation for her 2013 wedding.  She chalked it up to getting a little older or “being out of shape.”  But continuing symptoms finally led her to a neurologist who ran a battery of tests, culminating with a full genetic panel.

“The first time I heard of FA was the day I was diagnosed,” Harvey said. “FA has changed my perspective. Now, I live more in the moment than worrying about all the things in the future.

“On the days when I stumble a little more, my speech is slurred and I’m angry that my body is not behaving the way I’d like, my son is a fantastic reminder that I’m still capable of amazing things.  He’s very humbling.”

In his closing remarks Dr. Clifton Gooch, professor and chair of neurology at the USF Health Morsani College of Medicine, encouraged continued collaboration in the fight to find effective treatments and a cure for Friedreich’s ataxia.

USF’s Dr. Gooch closed the symposium by emphasizing the tremendous progress made in the research and development of lead drug candidates for Friedreich’s ataxia and encouraging all to continue to carry on the fight against the disease with laser focus.

“When pharma becomes engaged, that means the research is good enough to put smart money behind the disease to get a drug to market,” Dr. Gooch said. “There is more than just a glimmer of hope. We’re on the cusp of great possibilities… We look forward to the day when Friedreich’s ataxia will become a historical footnote like smallpox.”

For more information on the FARA patient registry, which provides notices about new clinical trials, go to http://www.curefa.org/patient-registry

Dr. Gooch, second from left, moderated the question and answer session with patients, l to r, Jade Perry, Erin O’Neil, Kendall Harvey, and Chris Nercesian.

FARA ambassador Kyle Bryant with Dr. Theresa Zesiewicz, director of the USF Ataxia Research Center.

Kyle Bryant with Sam Bridgman, who recently received a full scholarship to attend the graduate program at the USF Muma College of Business.

L to R: FARA President Ron Bartek; Dr. Clifton Gooch, chair of USF Health Neurology; Dr. Jodi Cook, vice president of operations, Agilis Biotherapeutics; Dr. Robert Molinari, founder and CEO of Retrotope; Dr. Jeffrey Sherman, CMO, Horizon Pharma; Dr. Theresa Zesiewicz, director, USF Ataxia Research Center; and Dr. Colin Myer, CMO, Reata Pharmaceutical.

Photos by Eric Younghans, video by Sandra C. Roa, USF Health Communications and Marketing

The first of its kind, an investigational drug, may enhance the body’s stem cell response at the site of cardiovascular injury  

TAMPA, Florida (Feb. 20, 2013) – Cardiovascular disease specialists at Florida Hospital Pepin Heart Institute and Dr. Kiran C. Patel Research Institute affiliated with the University of South Florida announced today they have enrolled their first two patients into the clinical trial of a novel gene therapy for the treatment of heart failure after ischemic injury.  The therapy may promote regeneration of  heart tissue by encouraging the body to deploy more stem cells to the injury site in patients who are suffering from heart failure.

Dr. Charles Lambert, Medical Director of Florida Hospital Pepin Heart Institute and Dr. Leslie Miller, Director of the USF Heart Institute, are leading the way for the randomized, placebo-controlled trial, which spans 10 sites across the United States. The study, called the STOP-HF, will enroll 90 patients nationwide.

Dr. Leslie Miller, director of the USF Heart Institute, confirms the exact location of the catheter tip as an injection map is drawn precisely detailing gene therapy delivery sites in the heart.

Heart failure (HF) happens when the muscles of the heart becomes weakened and cannot pump blood sufficiently throughout the body.  The injury is most often caused by inadequate blood flow to the heart resulting from chronic or acute cardiovascular disease, including heart attacks.   Considerable scientific evidence has emerged over the past decade demonstrating the high therapeutic potential of stem cell-based regenerative medicine for a host of diseases.  Heart failure is a leading cause of death, disability and hospitalization.

Dr. Charles Lambert is performing the gene therapy by direct injection into the heart using an investigational system in the catheterization laboratories at Florida Hospital Pepin Heart Institute.

“Pepin Heart and Dr. Kiran C. Patel Research Institute and USF are exploring and conducting leading-edge research to develop break-through treatments long before they are even available in other facilities,” said Dr. Lambert.  “Stem cells have the unique ability to develop into many different cell types, and in many tissues they serve as an internal repair system, dividing essentially without limit to replenish other cells. This trial is unique in that it uses gene therapy to turn on a process leading to cell regeneration rather than simply administering stem cells directly.”

Dr. Miller (right), national principal investigator for the STOP-HF trial, is collaborating with Dr. Charles Lambert, medical director of Pepin Heart Institute Florida Hospital, on the local gene therapy study. This is the first of several regenerative medicine trials that will team USF Health and Florida Hospital.

“This is the beginning of a new era in cardiovascular therapies,” said Dr. Leslie Miller, national principal investigator for the trial and professor of cardiovascular sciences at the USF Health Morsani College of Medicine. “Targeted gene and cell therapies delivered directly into the heart hold promise for helping to regenerate tissue, reduce injury and restore heart function.  USF Health, working with our partners, will find new ways to diagnose and treat patients, with the aim of reducing and ultimately harnessing the global impact of heart disease.”

Dr. Lambert injects one of multiple doses of medication containing the gene into a catheter inserted into the heart wall. With the assistance of contrast imaging, the gene therapy is carefully targeted to sites in the heart tissue with the potential for rejuvenation.

The trial, sponsored by Juventas Therapeutics,  a double-blinded Phase II study evaluating the safety and effectiveness of the drug JVS-100 in patients with ischemic heart failure.  JVS-100 is the name of the gene therapy that directs the heart muscle to produce Stromal cell-Derived Factor 1 (SDF-1), a protein that has been shown to repair damaged tissue in the body through the recruitment of circulating stem cells to the site of injury, prevention of ongoing cell death and restoration of blood flow.

Earlier this year, Juventas reported results from its Phase I study in Class III ischemic heart failure patients.  In addition to meeting the primary safety endpoint, patients in the study who received the drug demonstrated clinically significant improvements in exercise levels at the 12-month mark.   Other prominent institutions participating in the trial include Columbia University Medical Center, the University of Utah, the Lindner Center for Research at the Christ Hospital, and the Minneapolis Heart Institute Foundation.

Dr. Lambert, foreground, and Dr. Miller, back, watch the monitor displaying images of the patient’s heart.

Jadie Heberlein, clinical research nurse coordinator for the USF Heart Institute, monitors the gene therapy injections of patients enrolled in the STOP-HF case from the cardiac catheter laboratory control room at Florida Hospital Pepin Heart Institute.

Photos by Daniel W. Baker, Florida Hospital Tampa

About Florida Hospital Pepin Heart Institute and Dr. Kiran C. Patel Research Institute

Florida Hospital Pepin Heart Institute is a free-standing cardiovascular institute providing comprehensive cardiovascular care with over 76,000 angioplasty procedures and 11,000 open-heart surgeries in the Tampa Bay region.  Leading the way with the first accredited chest pain emergency room in Tampa Bay, the institute is among an elite few in the state of Florida chosen to perform the ground breaking Transcatheter Aortic Valve Replacement (TAVR) procedure. It is also a HeartCaring designated provider and a Larry King Cardiac Foundation Hospital. Florida Hospital Pepin Heart Institute and the Dr. Kiran C. Patel Research Institute, affiliated with the University of South Florida (USF), are exploring and conducting leading-edge research to develop break-through treatments long before they are available in most other hospitals. To learn more, visit www.FHPepin.org

About USF Health

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities. For more information, visit www.health.usf.edu

About Juventas Therapeutics

Juventas Therapeutics, headquartered in Cleveland, OH, is a privately held clinical-stage biotechnology company developing a pipeline of regenerative therapies to treat life–threatening diseases. Founded in 2007 with an exclusive license from Cleveland Clinic, Juventas has transitioned its therapeutic platform from concept to initiation of mid-stage clinical trials for treatment of heart failure and critical limb ischemia. Investors include New Science Ventures, Takeda Ventures, Triathlon Medical Venture Partners, Venture Investors, Early Stage Partners, Fletcher Spaght Ventures, Reservoir Venture Partners, Glengary, The Global Cardiovascular Innovation Center, Tri-State Growth Fund, North Coast Angel Fund, X Gen Ltd., JumpStart Inc., and Blue Chip Venture Co. The company has received non-dilutive grant support through the Ohio Third Frontier-funded Cleveland Clinic Ohio BioValidation Fund, Global Cardiovascular Innovation Center and Center for Stem Cell & Regenerative Medicine.

Media contacts:  
Jennifer McVan, Media Relations Manager
Florida Hospital, Tampa Bay Division
(813) 615-7395 (direct)  or (813) 373-9505 (cell)
Jennifer.Mcvan@ahss.org

Anne DeLotto Baier, USF Health Communications
University of South Florida
(813) 974-3303 or abaier@health.usf.edu

Several clinical trials starting at USF Health’s new Heart Institute this year will offer gene and stem cell therapy approaches to healing damaged hearts

Over the past 18 months, David Skand has been hospitalized four times, twice in intensive care. In June, the 70-year-old Tampa Bay Downs racetrack veterinarian found himself in the hospital once again. This time was different, though. This time he was filled with hope.

Skand is the first of 10 USF Health patients enrolled in a clinical trial for a genetically-engineered drug designed to treat chronic heart failure. The drug, developed in Shanghai, China, signals a patient’s own cells to remodel the heart.

Senior research nurse Bonnie Kirby speaks with trial participant David Skand and USF Health Heart Institute Director Dr. Leslie Miller.

It is the first of several trials getting under way at USF Health’s new Heart Institute. The institute, which was recently awarded $8.9 million in state and county funding, is focused on regenerative medicine using the latest in gene and stem cell therapy, as well as genomics-based personalized medicine.

“This is a significant change in thinking and goals,” says USF Health Cardiovascular Sciences Chair Dr. Leslie Miller, a renowned cardiologist and leading international specialist in heart failure and transplantation who leads the institute. “We are not just helping improve heart function, we are driving the heart’s native repair mechanisms.”USF is one of 10 sites for the randomized, double-blind study—the first test of the drug in the United States. For some patients, the drug, called Neucardin, could mean the difference between a heart transplant and a simple drug infusion.

Of the 120 patients who will eventually be enrolled in the study, 80 will receive the active form of the drug, while 40 will receive a placebo.

Dr. Leslie Miller says it is important for patients, like David Skand, to hear from him, as well as the research coordinator, about the risks and benefits of a trial.

“It’s thrilling,” says Skand, who was diagnosed with chronic heart failure in 1993. “I think this is going to help a lot of people in this country.”

He’s not worried about the possibility of receiving the placebo. “I have a 66 percent chance of getting it,” he says with confidence. “But the point is, you are still getting evaluated by the top doctors and the top nurses and undergoing really tremendous diagnostic procedures every day.”

For eight hours a day over 10 days in late June, Skand received either the drug or placebo through a small subcutaneous cathether. Studies to date show minimal side effects from the drug, occasionally a little nausea. Doctors continue  to follow Skand closely since he left the hospital after the extended infusion, particularly in the first six months when the greatest change in heart function would likely occur.

“The best would be an improvement in my ejection fraction,” Skand says, referring to the amount of blood his heart pumps out with every beat. “That would make a big difference for me. I’d be less tired; I could do more things, like walking and climbing stairs. And it would help my mental outlook a great deal.”

A radiologist at the institute reads a CT scan of the heart.

The Neucardin trial is the first of five planned trials—three gene therapy trials and two stem cell trials—at the institute this year. The trials are focused on preventing and reversing disease processes. There’s also a major study in partnership with the American College of Cardiology (ACC) to identify genes that are markers of atherosclerosis and other forms of coronary artery disease.

The need for new diagnostic tools, such as the use of genomic markers to detect and predict disease, and new therapies, such as stem cell and gene therapy, is indisputable. In Florida alone, cardiovascular disease accounts for 40 percent of all hospitalization and deaths. Estimates put the state’s costs for cardiovascular care at $17 billion by 2020.

But the problem isn’t isolated to Florida. According to Miller, cardiovascular disease is the biggest health risk in the world.

“The data is unequivocal. One in four people in the U.S. have cardiovascular disease. By 2020, it will be one in three,” he says. “The new Heart Institute is a critical step toward saving lives by finding new diagnostic tools that will allow earlier detection and better prevention, as well as new and improved therapies to improve outcomes.”

Patients enrolled in the Neurocardin trial are closely monitored after leaving the hospital, particularly in the first six months.

The ACC selected the Heart Institute as its partner for the first-ever trial linking genomic screening with its clinical database of patients.

“The ACC has millions of patients enrolled in registries and all the data for every type of cardiovascular disease,” Miller says. That data could help researchers identify individuals at risk for disease, allowing doctors to intervene long before a heart attack.

It could even help identify, early-on, children who may be at risk for developing the same heart condition as their parents.

“We want to do some out-of-the-box thinking about interventional treatments,” Miller says. “We might be able to introduce a statin at an early age to retard the development of atherosclerosis.”

Genetic markers have already been used in other fields to predict the likelihood of disease and introduce interventional treatments.

Cancer researchers, for example, have found that a significant percentage of women with breast cancer carry the genetic marker BR2a. The correlation is so strong, Miller says, that an increasing number of women who carry the gene are choosing to undergo a double mastectomy to prevent or reduce their risk for the disease.

Along with understanding risk, genetic discoveries could help doctors identify which treatments are most effective for individual patients as well as provide insight on appropriate dosing.

The gene and stem cell therapy trials offered by the institute will focus on preventing and reversing cardiovascular disease processes.

It’s the future of cardiovascular care and it places USF at the center of some of the most advanced research in the world, which is attracting leading scientists.

In March, Dr. Jennifer Hall, a nationally prominent cardiovascular genomics researcher joined the institute in March.  Her work in translational genomics—using a patient’s own genetic code to guide medical care—will be key to the ACC study.

But, USF Health’s focus on personalized medicine isn’t limited to heart disease. In June, Dr. Stephen Liggett, a nationally prominent researcher in genomics-based personalized medicine,  joined USF Health as associate vice president of personalized medicine and director of the Center for Personalized Medicine and Genomics.  Liggett’s initial collaborations will include Miller’s work at the Heart Institute.

“This field is moving so rapidly,” says Miller, calling this the most exciting time of his career. “A tube of blood allows us to have your whole DNA analyzed—a huge array of data to put in usable form for doctors to take care of patients.”

Skand, a racetrack veterinarian, says the new drug could make a big difference, enabling him to do more things and improving his outlook on life.

It’s the kind of research that could revolutionize healthcare, according to Dr. Stephen K. Klasko, CEO of USF Health and dean of the Morsani College of Medicine.

“We believe that the technology developed here will herald a new day and that USF Health will be able to partner with the best industry and academic partners throughout the world to develop these new personalized and genetic approaches to health.”

Postscript:   Dr. Skand notes he has felt much better in the initial months following the drug infusion, but neither he nor the healthcare practitioners involved in the blinded clinical trial will know whether he received active drug for likely a year.

Story by Ann Carney/Reprinted from USF Magazine,  Fall 2012
Photos by Eric Younghans, USF Health Communications