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ASU Biodesign Institute receives $5.2M from Michael J. Fox Foundation to advance fight against Parkinson's

January 13, 2022

Grants will be used to explore 3 pioneering treatments

The Michael J. Fox Foundation has awarded three new grants totaling $5.2 million to Arizona State University to explore three pioneering treatments for Parkinson’s disease.

The awards will fund research led by Principal Investigator Jeffrey Kordower, each targeting underlying causes of the disease, which currently affects nearly 1 million people in the U.S. alone.

The new projects focus on two primary hallmarks of Parkinson’s disease: the loss of dopamine-producing neurons in the brain and the accumulation within nerve cells of a misfolded form of the protein alpha-synuclein (α-syn).

Jeffrey Kordower

Kordower is the founding director of the ASU-Banner Neurodegenerative Disease Research Center at Arizona State University and the Charlene and J. Orin Distinguished Director at the Biodesign Institute.

Parkinson’s disease is a leading neurodegenerative ailment, whose symptoms include rigidity, tremors and difficulty with balance and walking. In many cases, problems with movement are accompanied by serious cognitive impairment, including dementia.

Currently, the number of patients living with Parkinson’s disease exceeds those living with multiple sclerosis, muscular dystrophy and ALS (Lou Gehrig’s disease) combined. By 2040, the disease is expected to affect 14 million individuals worldwide.

While some treatments exist for the constellation of movement disorders common in Parkinson’s patients, the most crippling aspect — severe cognitive impairment — remains untreatable at present.

“Professor Kordower’s approaches to the treatment of this devastating affliction qualify as truly revolutionary,” said Joshua LaBaer, executive director of the Biodesign Institute at ASU. “The brain is our most critical organ, essential to all bodily function as well as the repository of our selfhood. Replacing disease-damaged cells and selectively targeting disease-linked protein accumulations are techniques rapidly moving from the realm of science fiction to science fact.”

Exploring an enigma

Parkinson’s disease is a highly diverse disorder, affecting individuals in different ways.

Although a variety of genetic mutations are associated with the disease, few of these are hereditary, occurring in just 10–15% of patients. In some cases, environmental factors, including head injury or pesticide exposure may be involved. For most, the exact causes of the disease remain shadowy.

Though many mysteries persist, two hallmarks of Parkinson’s disease have long been recognized. The first is loss of the vital neurotransmitter dopamine in a brain region called the striatum.

Among its many functions, dopamine is used to ferry information between nerve cells. The dopamine system is involved in both movement and emotional response to stimuli, and is essential for physical and mental well-being. Parkinson’s disease destroys dopamine-producing, or dopaminergic, neurons in a specific region in the midbrain, known as the substantia nigra.

The second hallmark of the disease is the accumulation within nerve cells of α-syn. While this protein is necessary for proper brain function, an overabundance of α-syn, in an aberrant, misfolded form, can wreak havoc in the nervous system. Once α-syn pathology has taken root in a single cell or small cluster of cells, the process spreads like a contagion to neighboring cells, which in turn begin producing aberrant α-syn in a destructive cascade.

It is believed that deregulated dopamine levels and accumulating α-syn act synergistically in a vicious cycle, causing synaptic dysfunction and progressive neurodegeneration. In addition to treating the motor effects of the disease, a therapy targeting excess α-syn holds the promise of arresting the transition to Parkinsonian dementia.

Plug-and-play neurons

Neuronal loss in the brain is responsible for a broad range of serious afflictions, many associated with advancing age, a primary risk factor. Unlike other cell types in the body, neurons in most cases do not naturally regenerate. The large-scale depletion of neurons caused by Parkinson’s disease results in increasing physical decline.

Researchers continue to explore strategies designed to protect neurons from the ravages of Parkinson’s and other neurodegenerative diseases. But what if depleted neurons could be replaced with fresh, dopaminergic neurons? This is the rationale behind two of the new studies.

Kordower has been on the forefront of research into so-called neural grafting, in which stem cells are directly implanted in the brain. Earlier research by Kordower and others has demonstrated that under proper conditions, implanted cells can develop into the appropriate form of functional neuron, spread their nervous tentacles through damaged tissue, reconnect circuitry disabled by disease and restore function.

The delicate techniques involved in successful neural grafting are still being optimized but encouraging data have electrified the research community and could provide momentous advances in the fight against Parkinson’s and other neurodegenerative diseases.

Graphic shows the implanting of stem cells in a region of the brain known as the substantia nigra


The above graphic shows the implanting of stem cells in a region of the brain known as the substantia nigra. Graphic by Shireen Dooling

Brain trust

The first study is a human clinical trial, in collaboration with several centers, including the Barrow Neurological Institute in Phoenix. The approach involves infusing specially designed stem cells into the striatum where dopamine is lost. This project will be conducted in collaboration with Patrik Brundin with the Van Andel Institute, Michigan, and Virginia Mattis with Fuji-CDI, Wisconsin.

Unlike neurons and other highly specialized cell types, stem cells have the remarkable ability to develop into any cell type in the body, under proper conditions. The stem cells used for the brain implants begin their lives as blood cells. A laboratory treatment process causes these cells to undergo de-differentiation into stem cells known as induced pluripotent cells.

Research has shown that implanted cells of this type can recognize their location in the brain, develop into the proper cell type — in this case, nigral neurons — and begin dispensing dopamine, just as their naturally-occurring counterparts did before they were destroyed.

Dr. Paul Larson from the University of Arizona will perform the neurosurgeries at Barrow Neurological Institute, which will ease the patients’ burden by having them receive their surgery and imaging procedures at the same institution; a unique organization made possible by the colleagueship and generosity of Dr. Michael Lawton, CEO of Barrow Neurological Institute.

Patients who receive one or two doses of cells will be evaluated using PET scans and will be periodically re-examined to identify any adverse effects of the procedure and to assess the effectiveness of the therapy in treating symptoms of the disease. This method may not be effective in all cases of Parkinson’s, especially those who received the treatment too late because their brains were too severely damaged by the disease to recover. Because of the complexity of Parkinson’s disease, other factors may be undermining the dopamine system, and teasing out the results is challenging.

The current study aims to clarify and fine-tune the implantation approach by selecting patients with perceptible deficit due to Parkinson’s disease but not so severe that the damage is irreparable. Secondly, the study will attempt to simplify the picture by focusing on a select subset of Parkinson's patients, namely those with a specific mutation known as a Parkin mutation.

Parkin is a genetic mutation that causes the motor deficits seen in spontaneously occurring, or idiopathic, Parkinson’s disease. Unlike these patients, however, those with Parkin mutations typically display only the classic Parkinsonian symptoms because their disease is pathologically limited to degeneration of the dopamine system. This makes them ideal subjects for a clinical trial to restore dopaminergic cells in the striatum.

“We can transplant stem cells that are, by all accounts, like the nigral neurons that die in Parkinson’s disease,” Kordower said. “They have the same chemical properties; they have the same genetic material that tells them where to go.”

Patients receiving the new cells are expected to show improvements in symptoms in six to 12 months. Successful results in the clinical trial of Parkin mutation cases will thereby encourage further trials in a wider population of Parkinson’s patients.

Neural alchemy

The second study takes on an even more radical approach to addressing dopamine deficit. This recently discovered technique also aims to produce dopaminergic neurons to replace those depleted in the substantia nigra, but instead of inducing laboratory stem cells to become neurons and then implanting them, the technique converts supportive cells in the brain known as astrocytes into dopaminergic neurons.

Although neurons in the brain often grab most of the attention in the neuroscience community, astrocytes are an underappreciated cell type with many important functions in the central nervous system. They help maintain the blood-brain barrier, modulate neuroinflammation and release factors that stimulate the growth of nervous tissue.

Astrocytes are attractive cell candidates for reprogramming as they lie in the neural vicinity of neurons and are liberally distributed throughout the brains of all mammals. Indeed, the astrocyte population accounts for about half of the total cells in the brain.

Researchers have found that treating astrocytes to deplete a specific RNA-binding protein known as PTB can induce these cells to transition into new neurons capable of repopulating neural circuits damaged by disease. The current study will advance the quest to successfully convert midbrain astrocytes to dopaminergic neurons, reconstitute injured nigrostriatal circuits, restore proper dopamine levels and prevent or reverse the characteristic symptoms of Parkinson’s disease in a pre-clinical animal model of Parkinson’s. These experiments will be guided by Fluorodopa PET scan imaging, which will be done in collaboration with the Barrow Neurological Institute.

Housekeeping in the brain

The last of the three projects, in collaboration with ASU-Banner co-principal investigators Anne Messer and David Butler, of the New York Stem Cell Institute, targets α-syn accumulation in the brain, using a gene therapy technique. Here, a kind of engineered antibody known as a nanobody will be introduced to reduce α-syn.

One goal of the pre-clinical study is to demonstrate that nanobodies can successfully transduce cells throughout the brain, target accumulations of α-syn, bind with them and shuttle them to a cell structure known as the proteosome, where they are destroyed, much like a corrupted file being dragged to the garbage icon on a computer desktop.

Researchers are hopeful that global expression of the nanobodies following their injection in the cisterna, a region near the brainstem, will result in decreased α-syn load in specific areas of the cerebral cortex associated with cognitive decline in Parkinson's disease.

Biodistribution and proper functioning of nanobodies will be further explored using a human brain organoid system in the laboratory. Should the technique prove successful, researchers plan to pursue FDA approval for its use in clinical trials under Investigative New Drug status.

Top image: Among its many functions, dopamine is used to ferry information between nerve cells. The dopamine system is involved in both movement and emotional response to stimuli and is essential for physical and mental well-being. Parkinson's disease destroys dopamine-producing, or dopaminergic, neurons in a specific region in the midbrain, known as the substantia nigra. Image courtesy of The Biodesign Institute at Arizona State University

Richard Harth

Science writer , Biodesign Institute at ASU

480-727-0378

 
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Creating the future of Arizona

January 13, 2022

How ASU is helping bring new high-wage jobs to Arizona and increase the state's economic output through the New Economy Initiative

For generations, every Arizona schoolchild learned that the state’s economy is based on the five Cs: cattle, cotton, copper, climate and citrus.

While they worked well for the Grand Canyon State in its first hundred years, the 21st century requires coders and engineers for Arizona to stay competitive and resilient through the type of shocks the past 20 years have dealt.

Gov. Doug Ducey and the state Legislature have funded a plan for the state’s three universities to develop a coordinated response to attract high-tech industry, drive job creation and make Arizona families prosperous.

It’s called the New Economy Initiative. Its goals are to create 40,000 new high-wage jobs by 2041, increase economic output to $6.9 billion by 2032 and double the return on the state’s investment by the same year.

The endgame is to pivot Arizona’s economy away from housing growth and tourism to something that is resilient to economic downturns, pandemics and whatever else the 21st century has in store.

Video by Ken Fagan/ASU News

“All of us — the citizens of the state, the Legislature, the governor, chambers of commerce — all said, we have to do something and we have to do something collectively,” said Sally C. Morton, the executive vice president of Arizona State University’s Knowledge Enterprise.

Morton advances the university’s research priorities and drives corporate engagement, economic development, global initiatives, strategic partnerships and technology transfer on behalf of the university.

“And the state universities should play a central role in this,” she said.

Each university has been given distinct roles to play. Each role aligns to their traditional strengths. Northern Arizona University will expand its capacity to address health care worker shortages in nursing, allied health and mental health education programs. The University of Arizona is launching its “One Health” initiative that leverages the university’s medical, veterinary, engineering and cooperative extension programs to address community and health care needs across the state.

And at ASU, engineering will play a very big role, but it’s just one part of the university’s efforts.

ASU’s role

Knowledge Enterprise is coordinating ASU’s response to the New Economy Initiative. Beyond engineering, the university’s Academic, Learning and Knowledge enterprisesThe Academic Enterprise encompasses everything to do with degree-seeking students and the faculty who teach them. The Learning Enterprise is ASU’s lifelong learning ecosystem, designed for all learners no matter what stage of life (outside of those seeking degrees) — from kindergartners to mid-career professionals to retired people. The Knowledge Enterprise advances research, corporate engagement, economic development, entrepreneurship, international development and technology transfer. will be involved.

Budgeting and tracking dollars, and communicating to the state what the university is doing and the impact it is having, are also important parts of ASU’s effort.

The state Legislature is providing $33.4 million in ongoing funding and $18.8 million in one-time funding to ASU for the initiative.

The university is doing three things

1. Growing the Ira A. Fulton Schools of Engineering.

The Fulton Schools have hired 16 more faculty than usual on top of new hires.

“That’s a big number,” Morton said.

In addition to hiring new faculty, ASU has been buying equipment, placing it and renovating space for it. The newest acquisition is an atomic layer depositing tool, which allows engineers to deposit materials on a computer chip in a layer as thin as one-millionth of a human hair. It has to be in a clean room

2. Focusing on student success and workforce development.

This means training students in skills that are needed in a modern workforce and upskilling existing workers, as well as providing the means for people to move into the new economy.

For example: “Someone in the workforce who thinks, boy, if I could get into microelectronics, I could really support my family better,” Morton said.

3. Building five science and technology centers.

They will be physical centers with faculty and students, but also magnets for industry to come and present the most current problem they need solved.

“We solve that with our students, faculty as well as the industry partner,” Morton said. “And then together, we push the results out. … So it kind of focuses the work, if you will.”

ASU has already launched two science and technology centers (STC).

The MADE (Manufacturing, Automation and Data Engineering) STC focuses on the development of new technologies aimed at transforming manufacturing through 3D printing, robotics and automation, and new materials, with strong links to private industry support in aerospace, defense and space systems.

The AMPED (Advanced Materials, Processes and Energy Devices) STC is a national research resource for advancing new energy materials and device technologies in solar, batteries and electronics to market, growing industry engagement and workforce training.

3-D-printed objects

A 3D polymer printing sample, composed of nylon and carbon fiber, printed at ASU. Photo by Charlie Leight/ASU News

The other three science and technology centers will launch in 2022–23:

  • Extreme Environments will focus on management and technology opportunities associated with growing population centers, and research to engineer resiliency into the energy, water, materials and transportation systems in the built environment of future cities and regions.
  • Future Communications will develop physical information systems as the “internet of things” continues, and as users increasingly desire greater access, information and reliability in communications.
  • Human Performance will leverage regional, strength and technology opportunities to enhance physical and cognitive performance, medical prevention and intervention, and drive research from discovery to marketplace.

“I think of those science and technology centers as sort of the intellectual structure of the NEI,” Morton said. “The five areas were really based on both the strengths of Fulton Schools of Engineering and also a sense of where technology is going.”

Anecdotally, interest is high, according to the reactions Morton gets when she speaks to groups about the New Economy Initiative.

“Industry is really excited,” she said. “I go out and give these talks, and whether they’re virtual or in person I get business cards. People come up to me and say, ‘That sounds really cool. You know, I’ve got a company in X; how do I get connected to (a science and technology center)?’”

Partnerships and collaborations

In November 2019, Grace O’Sullivan, ASU’s vice president of corporate engagement and strategic partnerships, traveled with city of Phoenix and state officials to Hsinchu, Taiwan (considered Taiwan’s Silicon Valley), to help attract the Taiwan Semiconductor Manufacturing Company to the Valley.

Several months later, the chip giant selected Arizona and announced plans to build a $12 billion chip plant in Phoenix.

“They're bringing thousands of jobs to the Valley and an entire supplier network here,” O’Sullivan said. “The first thing they did was hire 200-plus engineering student graduates from ASU. And now we’re engaging with them on defining and scoping R&D projects, what the facilities are going to look like. They’re asking us for our curriculum and semiconductor training.”

ASU has partnerships and relationships with almost every tech giant in the state: Honeywell, Raytheon, Intel and dozens of others. Sometimes their engineers come to the university for help solving specific problems, like reprogramming a robot. Sometimes they’ll request more grads with specific skills, like 3D printing.

It has all been a dry run for the New Economy Initiative.

“We've been really laying the groundwork for many years ahead of time in aligning partners, getting the local community ready,” O’Sullivan said.

“From my perspective in the university, we’ve been cultivating partnerships like growing our engagements with Intel, SRP, APS, Mayo Clinic, Dignity Health ... ” she continued. “Now we have this organizing framework around the New Economy Initiative and our science and technology centers. This is a great way for our industry partners to connect on these really important themes for the new economy.”

ASU has secured close to $10 million in grants from the Department of Labor for workforce development. They are focused around IT skills, cybersecurity and advanced manufacturing. The university is creating apprenticeship programs and new models for how people are getting trained in the workforce — either new talent coming in or existing employees who need to be re-skilled.

“We are working with the state workforce office, municipal workforce offices, the city of Phoenix and our community college partners to create this entire pipeline of the talent that’s needed to feed the future,” O’Sullivan said.

Mayo Clinic and ASU have more than 165 jointly appointed members — those who work at Mayo Clinic and guest lecture or teach part-time at the university.

Exterior of Mayo Clinic building in Phoenix

One of ASU's local collaborations is with Mayo Clinic, which has Arizona locations in north Phoenix and Scottsdale.

“Now we really want to replicate that model with industry,” O’Sullivan said. “It’s a model that has a proven track record.”

Valley cities are starting to sit up and take notice that ASU makes things they want. The university is in talks with the cities of Peoria and Phoenix on how to design an innovation technology cluster in the northwest Valley.

“I think they’ve seen the success that ASU is able to bring to revitalize a region, for example, like in downtown Phoenix,” O’Sullivan said. “We are now being — maybe courted is too strong of a word — asked by cities to come and develop innovation zones or regional hubs in partnership with them.”

Upskilling

Meredyth Hendricks is head of upskilling within ASU’s Learning Enterprise, the university unit responsible for reimagining how to serve learners across their lifespan. Hendricks leads a team that collaborates with experts across the university to build and scale job-relevant education programs that serve two key purposes: giving learners the skills they need to succeed at every career stage, and providing employers with a more skilled workforce.

“Within the New Economy Initiative, we’re focused on catalyzing Arizona’s workforce to position learners and companies for success in Arizona’s new economy,” Hendricks said. “Our goal is to leverage ASU’s assets as a top-tier research university to build education programs that give workers the opportunity to learn in-demand job skills, from foundational professional skills to those related to cutting-edge technologies.”  

The Learning Enterprise has ambitious program development goals. The first type of programs are highly scalable courses that will reach learners across the state, including those already in the workforce. One initial focus for the team is developing a robust portfolio of courses related to professional skills (sometimes termed “soft skills”), such as critical thinking, emotional intelligence and teamwork. These are rarely taught comprehensively in school, but they’re critical across many roles. 

“Three out of four employers say that they have difficulty finding employees who have the professional skills their companies need,” Hendricks said. “This skills gap in the market presents an opportunity for ASU to have an impact. Moreover, these skills are not likely to be automated in the future because they are by nature human skills.”

Learning Enterprise will also be leading custom engagements with corporate partners and collaborators, including executive education, working directly with companies to address their specific workforce education goals.

“ASU faculty and researchers work at the forefront of industry innovation, and the opportunity to partner with Arizona companies to upskill their workforces is exciting. Custom partnerships can range from educating workers with entry-level skills to skills related to the frontier-technology, as that is the focus of the new Science and Technology Centers,” Hendricks said.

One example where ASU has already done custom education is with Mayo Clinic.

Mayo Clinic needed help onboarding new schedulers in an online and remote training environment, so it came to ASU. The university helped develop a new onboarding program to train these new hires.  

Typically ASU’s corporate partnerships are straightforward. Honeywell contacts the Polytechnic campus and lets it know it will need 10 3D printing engineers next year. Next year, the university delivers 10 newly minted engineers. Now, that type of interaction will be greatly expanded.

“By significantly expanding the number of individuals we reach with top-quality, job-relevant education, ASU will help develop the talent Arizona needs to improve its competitiveness.” Hendricks said. “The state has given us an ambitious assignment, and I think we’re up to the task.”

Engineering

With nearly 27,000 undergraduate and graduate students and 75 degree options offered on two campuses and online, the Fulton Schools of Engineering is the largest and most comprehensive engineering school in the United States.

Administrators of the Fulton Schools see two things as their greatest strength: their students and their faculty. Their plan to advance the New Economy Initiative is to rely on those strengths by beefing up both.

Engineering enrollment has skyrocketed at ASU, with undergraduate enrollment rising from more than 6,000 in 2010 to more than 20,000 in 2021. When they graduate, they move into companies and they start companies.

Because ASU is a research university, the faculty work on the cutting edge of technology. Think white lasers, medical devices and prosthetic limbs that can feel. Students are immersed in it, interning in industry or performing tasks like reprogramming a robot arm that a Raytheon supplier couldn’t complete, through the eProjects program.

ASU student engineers fix Raytheon robotic arm

A group of engineering students helped resurrect a Raytheon robotic arm in 2018. Raytheon delivered the non-working deburring robot to ASU in hopes that it could reprogram the device after the former integration company failed. In the 60-day time frame, engineering students were able to program, run and test the massive arm. Photo by Charlie Leight/ASU News

“They find translational pathways,” said Kyle Squires, dean of the Fulton Schools. “They connect into industry partners that basically help industries see the horizon of where their industry sector’s headed. It de-risks that process. It basically brings us into it. And that’s something universities are uniquely able to do. ASU has really leaned into that. I think that’s one area where ASU really has a competitive advantage. We can scale that through the NEI.”

ASU is hiring new faculty to support the New Economy fields and themes — most notable recently in materials sciences.

Squires expects not only that ASU faculty will work with industry, but that industry will participate at ASU.

“They might be a practicing engineer at Intel or Boeing or whatever,” Squires said. “And they teach a class once a year, maybe twice a year, whatever. How do we fortify that structure so that if you are that double-E (electrical engineering) PhD, and we’ve been connecting with you for quite some time around some topic in teaching or research or whatever the case. What if you were to scale that and think about it broadly? What does that look like?”

The ideas being catalyzed by the state’s investment were directions ASU has been moving in for some time.

“This is not some new, crazy wild idea,” Squires said. “This is a really important direction. Now we can accelerate. We can scale. We can increase the rate of faculty hires, and that’s good on the institution because the direction makes sense.”

Arizona is primed for prosperity.  

“That’s owing to ASU,” Squires said. “That's owing to all the partners in the Valley now to get to that next level. I can’t overstate it. This is the moment that we need to catalyze that transformation to that next level — that kind of really genuinely dynamic economies that we see around the country.”

“It’s a great example of the role that public universities can play to serve our communities and just wonderful that the state has come together in this way to say we need to change this,” Morton said. “We need to change this for the future for the state and moving forward.”

Top image of downtown Phoenix by Deanna Dent/ASU News

Scott Seckel

Reporter , ASU News