Clifton (Cliff) Gooch, MD, professor and chair of the USF Health Morsani College of Medicine’s Department of Neurology, was recently appointed to the national ALS Association Board of Trustees.  He is one of four new members of the 25-member national board.

The Association is the world’s largest private funder of research for amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease affecting nerve cells in the brain and spinal cord.

A leader in the ALS community, Dr. Gooch developed his interest in ALS at the beginning of his neurology training at Baylor University College of Medicine in Houston, Texas.  He has engaged in ALS research, clinical care, and administration throughout his career.

He began his career as a junior faculty member with Baylor’s ALS Center in the early 1990s, then moved to Columbia University in New York, NY, in 1999, where he was part of the Eleanor and Lou Gehrig ALS Center and the Columbia Motor Neuron Research Center. Since 2008, he has led the Department of Neurology at the University of South Florida in Tampa, Fla. The university has one of the largest ALS clinical care and clinical research centers in the Southeast.

Dr. Gooch has held numerous leadership positions at USF, including establishing and directing the USF Neuroscience Collaborative for interdisciplinary research and founding the USF ALS Center. During his tenure, the Neurology Department more than tripled in size, greatly expanded its research portfolio, and now conducts more than 100 clinical trials a year.

In addition to his national leadership position as president-elect of the Association of University Professors of Neurology, Dr. Gooch serves as treasurer of the American Neurological Association (ANA) Board of Directors. He is a fellow of both the American Academy of Neurology and the ANA, and highly sought as a speaker by many organizations across the country and internationally.

A new University of South Florida preclinical study finds that the regenerative cell therapy boosts motor nerve cell survival by repairing the blood-spinal cord barrier

TAMPA, Fla. (April 2, 2019) — Transplantation of human bone marrow-derived endothelial progenitor cells (EPCs) into mice mimicking symptoms of amyotrophic lateral sclerosis (ALS) helped more motor neurons survive and slowed disease progression by repairing damage to the blood-spinal cord barrier (BSCB), University of South Florida researchers report.

The study was published March 27 in Scientific Reports, one of the Nature journals. The findings contribute to a growing body of work exploring cell therapy approaches to barrier repair in ALS and other neurodegenerative diseases.

Human bone marrow-derived endothelial progenitor cells in vitro

The progressive degeneration of nerve cells that control muscle movement (motor neurons) eventually leads to total paralysis and death from ALS. Each day, an average of 15 Americans are diagnosed with the disease, according to the ALS Association.

Damage to the barrier between the blood circulatory system and the central nervous system has been recognized as a key factor in the development of ALS. A breach in this protective wall opens the brain and spinal cord to immune/inflammatory cells and other potentially harmful substances circulating in peripheral blood. The cascade of biochemical events leading to ALS includes alterations of endothelial cells lining the inner surface of tiny blood vessels near damaged spinal cord motor neurons.

This latest study by lead author Svitlana Garbuzova-Davis, PhD, and colleagues at the USF Health Morsani College of Medicine’s Center of Excellence for Aging & Brain Repair, builds upon a previous study showing that human bone marrow-derived stem cells improved motor functions and nervous system conditions in symptomatic ALS mice by advancing barrier repair. However, in that earlier USF study the beneficial effect was delayed until several weeks after cell transplant and some severely damaged capillaries were detected even after a high-dose treatment. So in this study, the researchers tested whether human EPCs – cells harvested from bone marrow but more genetically similar to vascular endothelial cells than undifferentiated stem cells – would provide even better BSCB restoration.

Svitlana Garbuzova-Davis, PhD

ALS mice were intravenously administered a dose of human bone-marrow derived EPCs.  Four weeks after transplant, the results of the active cell treatment was compared against findings from two other groups of mice:  ALS mice receiving a media (saline) treatment and untreated healthy mice.

The symptomatic ALS mice receiving EPC treatments demonstrated significantly improved motor function, increased motor neuron survival and slower disease progression than their symptomatic counterparts injected with media. The researchers suggest that these benefits leading to BSCB repair may have been promoted by widespread attachment of EPCs to capillaries in the spinal cord. To support this proposal, they point to evidence of substantially restored capillaries, less capillary leakage, and re-establishment of structural support cells (perivascular astrocytes) that play a role in helping form a protective barrier in the spinal cord and brain.

Further research is needed to clearly define the mechanisms of EPC barrier repair.  But, the study authors conclude: “From a translational viewpoint, the initiation of cell treatment at the symptomatic disease stage offered robust restoration of BSCB integrity and shows promise as a future clinical therapy for ALS.”

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

Article citation:
Svitlana Garbuzova-Davis, Crupa Kurien, Edward Haller, David J. Eve, Stephanie Navarro, George Steiner, Ajay Mahendrasah, Surafuale Hailu, Mohammed Khatib, Kayla J. Boccio, Cesario V. Borlongan, Harry R. Van Loveren, Stanley H. Appel and Paul R. Sanberg. Human Bone Marrow Endothelial Progenitor Cell Transplantation into Symptomatic ALS Mice Delays Disease Progression and Increases Motor Neuron Survival by Repairing Blood-Spinal Cord Barrier, Scientific Reports, March 27, 2019. https://doi.org/10.1038/s41598-019-41747-4.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two rare neurodegenerative diseases also considered as spectrum disorders, affect thousands of Americans every year.

ALS, a condition that effects nerves and muscles, and FTD, a disorder that causes changes in behavior and personality, language, motor skills and function, are associated with one another due to a common genetic mutation in multiple genes.

David Kang, PhD, professor of molecular medicine, in his laboratory at the USF Health Byrd Alzheimer’s Institute. He was the study’s lead author. 

However, researchers did not know exactly why that happened until a new research breakthrough at University of South Florida Health in Tampa, Florida.

A group of USF Health researchers found that a mutated ALS and FTD gene is pathologically linked to mitochondria dysfunction and TDP-43 pathology – causing problems for people affected by either disease.

The results of this study were published in Nature Communications Journal.

The study’s lead investigator David Kang, PhD, professor of molecular medicine and researcher at the USF Health Byrd Alzheimer’s Institute, said that this is a very important pathological link for ALS and FTD.

“Mutations in the ALS and FTD gene, called CHCHD10, are instigating dysfunction in the mitochondria, the cell powerhouse plants that produce the majority of the energy in the human body,” Dr. Kang said. “This gene allows TDP-43, a protein that’s part of the nuclear function, to exit the nucleus to get into the cytoplasm or cell body and cause TDP 43-pathology – which is relatively specific to ALS and FTD.”

While many genes cause ALS and FTD, this gene is the first one that’s been linked to mitochondria, Dr. Kang said. Dr. Kang and his team of researchers have worked on this study for two years, supported by grants from the Veterans Administration, National Institutes of Health and Florida Department of Health.

Dr. Kang (second from right) with some members of his research team. From left: JungA (Alexa) Woo, PhD, assistant professor; Courtney Trotter, graduate research assistant; and Tian Lu, PhD, postdoctoral research scholar, Department of Molecular Medicine, USF Health Morsani College of Medicine.

To come up with the results, the USF Health researchers studied worms, mammalian cell lines, primary neurons and mouse brains. The models allowed them to prove that the mutated gene is very important to the mitochondrial function, which the human body needs.

“We took the human gene, CHCHD10, and we put it into worms with a short life-span,” Dr. Kang said. “We used worms who lacked the CHCHD10 gene and had dysfunctional mitochondria, which, as a result, had motor problems and could not move properly. What happened was that the normal human gene helped the worms live longer – completely rescuing their abnormalities and restoring their mitochondria function and movement. However, when we put the single mutated gene that causes ALS and FTD into the worm, it did not rescue at all. They were still completely dysfunctional.”

The USF Health research team suggests that these results are critical to ALS and FTD research. This was the first study to show that the normal gene increases mitochondria function and the mutant gene increases mitochondria dysfunction. The normal gene is bound to TDP-43 protein and allows it to stay in the nucleus.

Alexa Woo, PhD

However, when TDP-43 pathology is outside the nucleus, it decreases mitochondria function and synaptic integrity, connecting points between neurons. Researchers said synapse loss occurs in all neurodegenerative diseases.

This is an important step into the right direction, but researchers at USF Health agree that there is more work to be done.

“I think ultimately, if we can understand how the neurodegenerative disease leads to aberrations at the molecular level, then we can potentially target specific molecules that induce pathology in ALS or FTD,” Dr. Kang said.

Photos by V.  Hysenlika

ALS mice improved with stem cell therapy; first step for science in finding better treatment  

TAMPA, Fla. (May 12, 2017) – Researchers at the University of South Florida show in a new study that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with the disease amyotrophic lateral sclerosis (ALS) by repairing damage to the  blood-spinal cord barrier.

In a study recently published in the journal Scientific Reports, researchers in USF’s Center of Excellence for Aging and Brain Repair say the results of their experiment are an early step in pursuing stem cells for potential repair of the blood-spinal cord barrier, which has been identified as key in the development of ALS. USF Health Professor Svitlana Garbuzova-Davis, PhD, led the project.

Previous studies in development of various therapeutic approaches for ALS typically used pre-symptomatic mice. This is the first study advancing barrier repair that treats symptomatic mice, which more closely mirrors conditions for human patients, Dr. Garbuzova-Davis said.

Svitlana Garbuzova-Davis, PhD, led the study.

Using stem cells harvested from human bone marrow, researchers transplanted cells into mice modeling ALS and already showing disease symptoms. The transplanted stem cells differentiated and attached to vascular walls of many capillaries, beginning the process of blood-spinal cord barrier repair.

The stem cell treatment delayed the progression of the disease and led to improved motor function in the mice, as well as increased motor neuron cell survival, the study reported.

ALS is a progressive neurodegenerative disease that affects neuronal cells in the brain and the spinal cord, which send signals to control muscles throughout the body. The progressive degeneration of motor neuron cells leads to death from ALS. More than 6,000 Americans each year are diagnosed with the disease.

Because stem cells have the ability to develop into many different cell types in the body, researchers at USF’s Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair have focused on using stem cells to restore function lost through neurodegenerative disorders or injuries.

Damage to the barrier between the blood circulatory system and the central nervous system has been recently recognized as a factor in ALS development, leading researchers to work on targeting the barrier for repair as a potential strategy for ALS therapy.

In this study, the ALS mice were given intravenous treatments of one of three different doses of the bone marrow stem cells. Four weeks after treatment, the scientists determined improved motor function and enhanced motor neuron survival. The mice receiving the higher doses of stem cells fared better in the study, the researcher noted.

The transplanted stem cells had differentiated into endothelial cells – which form the inner lining of a blood vessel, providing a barrier between blood and spinal cord tissue – and attached to capillaries in the spinal cord. Furthermore, the researchers observed reductions in activated glial cells, which contribute to inflammatory processes in ALS.

USF Health Morsani College of Medicine researchers Crupa Kurien, Avery Thomson, Dimitri Falco, Sohaib Ahmad, Joseph Staffetti, George Steiner, Sophia Abraham, Greeshma James, Ajay Mahendrasah, Paul R. Sanberg and Cesario V. Borlongan joined in the project. The study was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Read the full study here.

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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 Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida, established in 1956 and located in Tampa, is a high-impact, global research university dedicated to student success. USF is ranked in the Top 30 nationally for research expenditures among public universities, according to the National Science Foundation. For more information, visit www.health.usf.edu

News release by Vickie Chachere, USF Research and Innovation

Media contact: 
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303

Increased funding helps provide much-needed coordinated care to ALS patients and families across Florida. Access to care truly made a difference to Billie Jean Fogle. 

There’s no cure for the debilitating terminal disease known as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease), but access to comprehensive ALS care extends and improves patient’s lives, and also enhances the lives of their families. To help residents throughout Florida gain access to this care, the Florida Legislature passed the Bitner/Plante Amyotrophic Lateral Sclerosis Initiative of Florida during the 2013 session to provide $1 million to greatly expand services at those Florida clinics offering the highest level of comprehensive ALS Care.

ALS patient Billie Jean Fogle (left), was relieved to have access to personalized, comprehensive care, said her daughter Teresa Zeller (right). Photo courtesy of Teresa Zeller.

“This is a direct benefit to the patients and their families,” said Clifton Gooch, MD, professor and chair of the USF Health Department of Neurology and an ALS specialist. “Research has proven that a multidisciplinary approach to care prolongs the lives of ALS patients and improves the quality of their lives. However, the barrier for most ALS patient is access to that care, as our current medical system does not provide coverage for many of the key components of this treatment.”

The funding allowed the USF Health ALS Center, which opened October 2011, to double the number of patient appointments and to significantly shorten the patient wait list. The funding also allowed for similar expansions at the other comprehensive ALS centers sites in Florida, including the University of Miami, University of Florida Shands in Jacksonville, and the Mayo Clinic Jacksonville.

To help disperse care even further across Florida, the initiative is also pioneering a telemedicine component, using technology to provide visual interaction for patients with the many providers necessary to treat their disease.

Dr. Clifton Gooch at the opening of the USF Health ALS Center in 2011.

“The telemedicine component means that even ALS patients living in rural areas who can’t make it to one of the centers for their many appointments can now be monitored and treated between face-to-face clinic visits,” Dr. Gooch said.

The initiative will also facilitate more research toward improved treatment by increasing the number of patients enrolling in clinical trials.

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Teaming up makes the difference to ALS patients
ALS is a deadly disease that progressively paralyzes its victims, attacking nerve cells and pathways in the brain and spinal cord. Patients are robbed of the ability to walk, eat, speak and, eventually, breathe. Most live for just two to five years after diagnosis.

ALS patients require care from many specialists, including neurologists, speech therapists, physical therapists, respiratory therapists, nutritionists, and psychologists, among others. Coordinating the care within a single multidisciplinary team visit ensures patients will receive all the care that they need in a coordinated fashion. It also is much easier on debilitated ALS patients and their families, sparing them from making dozens of trips to separate appointments to see many specialists over time.

“A comprehensive multidisciplinary center provides under one roof all of the services ALS patients require, and that makes the biggest difference in the life of an ALS patient,” said Tuan Vu, MD, professor of neurology and director of the USF Health ALS Center.

“Funding allows us to bridge the access gap and provide much needed care for ALS patients,” Tuan Vu, director of the USF Health ALS Center.

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How big of a difference?
There was about three years between a diagnosis of ALS and death for Billie Jean Fogle.

But that short time was made much more comfortable – and maybe even prolonged – because of the ALS Center at USF Health, said Fogle’s daughter Teresa Zeller.

“Finding the USF Health ALS Center was wonderful,” Zeller said. “Traveling is so hard, nearly impossible really.”

Zeller said her mother connected with USF in April 2011 and was greatly relieved to have such personalized care.

“The biggest blessing for Mom was that the team was all there at one appointment, all of them in one room. They would go in and out of the room to talk to us, we didn’t move from specialist to specialist. It was a long morning for Mom but so much better than another clinic we visited. It was all in one place, but we were the ones who had to move within the building.”

The team approach is what really made the difference, Zeller said.

“They all worked together, instead of piecing together her care,” she said. “And the support staff really helped us follow up on the orders that came out of her appointments. We didn’t have a moment to make five phone calls to look into her respiratory therapy. They told us exactly who to contact.”

***
Building an initiative to improve access to ALS care
The impetus for seeking funding came when Wendy Bitner toured the USF Health ALS Center through the ALS Association’s Hope and Help Tours. Her husband, Florida State Rep. David Bitner, had recently died of ALS in September 2011.

When she asked how she could help, Dr. Gooch described the difficulty the Center has in securing funding every year and that the current annual funding allowed for a limited number of appointments for ALS patients. Bitner, together with Dr. Gooch and members of the ALS Association, framed a proposal for $1 million that would not only expand the ability of USF Health’s ALS Center to take additional patients but would also fund expansions at three additional centers across the state to help increase access to treatment and support for ALS patients throughout Florida.

David Bitner was highly regarded and his colleagues in Tallahassee did not hesitate to help shepherd the proposal through. The proposal was approved by the Florida Legislature in Spring 2013.

ALSA is administering the project and collecting data on the number of patients being seen at the four clinics.

Administration of the Initiative is unique: there is no single person charged with directing the Initiative, but a group of ALS experts from each of the centers instead guides the program.

“We are very democratic, and have created this round table approach, so that everyone has equal input,” Dr. Gooch said. “We all want to work together in an equitable way and avoid problems that come from decisions being based at one facility over another.”

***
Looking ahead
The hope, Dr. Gooch said, is that state elected officials will see the value in this and help grow the funding.

“We need to keep all of these centers open and running and spread these benefits all over the state,” Dr. Gooch said. “The academic comprehensive ALS centers participating in this initiative are unique because they are able to provide the highest level of expertise and the most comprehensive levels of care. ALS operations of this kind take years to develop and rely heavily on the resources and infrastructure of the academic medical center, which is why there are a limited number of centers.”

But continued funding will mean continued access to care and an increase in research opportunities, he added.

“The patient-care side of these ALS centers is only part of the operation,” Dr. Gooch said. “There is also a great deal of translational research, offering patients everywhere hope for a cure.”

***
How you can help
One way you can help is to join the local Walk to Defeat ALS, set for 9:30 a.m. Saturday, March 8, 2014. Click here for more information.

Dr. Clifton Gooch addressing supporters at the annual ALS Walk.

Sadie, a rescue dog from Project PUP, makes friends with Matt June, a patient of the USF ALS Center.

Patients visiting the USF ALS Center on April 5 were greeted with a wagging tail and soulful eyes begging for attention.

Sadie, a senior rescue dog from PROJECT PUP (Pets Uplifting People), was on hand to spend some time with patients while they waited and even during their clinical time with doctors and staff at the multidisciplinary clinic.

The Center plans to make Sadie, and possibly other canine friends, part of a pet therapy program at its monthly clinic housed within the USF Health Morsani Center for Advanced Healthcare, said Brittany Harvey, staff assistant and research support specialist for the ALS Center.

Sadie’s owner Christine Hamacher, a volunteer with Project PUP, said research has shown that interaction with good-tempered pets like Sadie can help calm the anxiety of patients and their families, who spend quite a bit of time being assessed by healthcare team members during their clinic appointments. “Just having her (Sadie) in the same room helps them to speak more comfortably and freely with doctors and staff,” Hamacher said.

Sadie may not know she’s doing all that.  Waiting in an exam room with patient Matt June and his wife Jackie, she appeared more than content to solicit hugs, get scratched behind her silky ears and dole out doggie kisses.

Matt and wife Jackie June with Sadie

The USF ALS Center, directed by Dr. Tuan Vu, opened in October 2010 as the first multidisciplinary university clinic of its kind in Tampa Bay and all of Central and West Florida.

About 200 patients a year visit the clinic, which is dedicated to developing new and effective therapies for ALS, or amyotrophic lateral sclerosis. Also, known as Lou Gehrig’s disease, the neurodegenerative disease progressively paralyzes the individual, attacking nerve cells and pathways in the brain and spinal cord.  The USF ALS Center belongs to the world’s largest ALS research network, the Northeastern ALS Alliance.

Photos by Eric Younghans, USF Health Communications