A key new ally in the search for Huntington’s disease treatments

With the new partnership between Roche and Isis Pharmaceuticals, Inc., reported here on April 11, the search for Huntington’s disease treatments has gained an accomplished and ambitious ally in the person of Luca Santarelli, M.D., Ph.D.

Dr. Santarelli, the 44-year-old head of neuroscience and small molecule research at Roche’s world headquarters in Basel, Switzerland, will oversee the Roche-Isis effort to bring Isis’s proposed gene-therapy drug to a long-awaited crucial clinical trial, tentatively scheduled to start in the first half of 2014.

A native of Italy, Dr. Santarelli in the early 2000s made an astounding discovery about Prozac-type antidepressants while conducting postdoctoral research at Columbia University in New York City: these drugs actually led to neurogenesis, the birth of new neurons in the brains of adults.

With these findings, Dr. Santarelli joined Nobel laureate Dr. Eric Kandel, Dr. Rene Hen of Columbia, and Dr. Fred Gage of the Salk Institute for Biological Studies in San Diego to found a company, Brain Cells, Inc., that focused on the development of novel antidepressants for stimulating neurogenesis.

In 2005, Dr. Santarelli joined Roche. He quickly rose in the company ranks and now oversees efforts to design drugs for brain disorders and related conditions, including schizophrenia, depression, Alzheimer’s disease, multiple sclerosis, spinal muscular atrophy, and neurodevelopmental disorders such as autism and Down syndrome.

Nature’s Trojan horses

Now, turning their attention to HD, Santarelli and Roche researchers will collaborate with Isis to speed progress towards the clinical trial, infusing $30 million into the project.

They also will seek ways to make the potential Isis drug easier for trial participants and eventual patients to absorb. Instead of Isis’s potentially riskier and certainly less comfortable method of implanting a quarter-sized port near the rib cage connected to a catheter running to the area of the spinal cord, Roche aims to create a drug that patients could take through an intravenous or subcutaneous (under the skin) injection. (It’s still too early to tell where in the body patients would receive such a potential subcutaneous injection.)

To design this kind of drug, Roche will use a so-called “brain shuttle,” a new approach to transporting drugs past the highly impermeable blood-brain barrier, which protects the brain from foreign objects.

The blood-brain barrier also makes it difficult for so-called large molecule drugs to enter the organ and thus has presented researchers with a major hurdle to treating brain disorders and diseases.

Dr. Santarelli, in a phone interview on April 22, was asked to explain the brain shuttle in everyday terms.

“It works by hijacking a biological system that is normally used to shuttle proteins into the brain,” he told me. “It uses cellular receptors outside the blood brain barrier and uses them as Trojan horses to take in a cargo.”

Dr. Luca Santarelli (photo courtesy of Roche)

The cargo could include an antisense oligonucleotide, or ASO, the specially designed piece of artificial DNA made by Isis that, in mice experiments, has reduced the amount of the harmful huntingtin protein in brain cells and produced a “Huntington’s holiday,” a disappearance of the symptoms.

“A cargo can be an ASO,” Dr. Santarelli continued. “It could also be a peptide or an antibody. Receptors are on the outside (of the blood-brain barrier), but they also move to the inside. They are built by nature to allow certain large molecules (to move in).”

Explaining the concept

No brain shuttle drug yet exists. I was eager to know exactly what kind of shuttle Roche might have in mind and how it could work with the ASOs.

However, because of the trade secrets involved in private drug research, Dr. Santarelli declined to comment.

Nevertheless, he emphasized that the brain shuttles are “built by nature to allow the transfer of large proteins inside the brain.” Different shuttles have different capacities, he added, and they work in a “controlled fashion.”

“The concept of proteins that shuttle large molecules has been known for a while,” he said, referring to the decade-plus research on the phenomenon.

Dr. Santarelli cited the example of the shuttle known as transferrin.

“We know that transferrin works in this way,” he said. “Transferrin is a protein that carries around iron in the bloodstream. Iron doesn’t go around freely. It’s absorbed and transferred around to the organs. It (transferrin) binds with iron – iron gets released into the brain.”

Advantages of the brain shuttle

By carrying an ASO into the brain in this revolutionary manner and avoiding the discomfort of a lumbar (lower-back) puncture or other long-term invasive approach, the brain shuttle approach helps drug discovery in two key ways.

First, it allows researchers to include people in clinical trials who previously were not eligible – namely, people genetically at risk for a disease but without symptoms. In terms of ethics and comfort, it is difficult to justify their participation because of the risk posed by invasive procedures.

With the brain shuttle, however, discomfort is reduced. So is the ethical barrier, because the injury risk diminishes.

Secondly, by including presymptomatic people in drug studies, researchers can measure how a drug affects a patient before the disease develops, thus providing clues about how to stop the disease from ever occurring.

Only a few years ago, this kind of approach to neurological drug research seemed futuristic. The lack of opportunities to participate in clinical trials and the absence of a strategy to prevent the disease in asymptomatic people have proved especially frustrating for the HD community, where people like me await in great fear the onset of a disease foretold by genetics.

A unique Alzheimer’s trial: intervening early

With Isis, Dr. Santarelli and Roche are working to raise the hope of preventing asymptomatic gene carriers from ever experiencing onset.

Roche is especially well-positioned because, as Dr. Santarelli pointed out, it focuses on both drug development and disease diagnostics.

Roche’s “strategic objective” is to intervene “as early as possible” in the course of the disease, he emphasized.

“As an organization, we’ve done this in Alzheimer’s,” he explained.

In developing its proposed Alzheimer’s drug, now under study in a clinical trial involving 800 patients, Roche has taken the unique step of including individuals who have not yet developed dementia, but have merely mild cognitive impairment, Dr. Santarelli said. (Click here for further background.)

In the trial Roche is using molecular testing to diagnose and select trial subjects at risk for Alzheimer’s. This is done by performing a lumbar puncture to obtain a sample of cerebral spinal fluid (CSF) to check the presence of amyloid, the substance that forms plaques in the brain of Alzheimer’s patients and is considered one of the causes of the disease.

If successful, the Roche drug will not only clear plaques from the brains of the Alzheimer’s patients but also delay (or stop) the progression of the disease, Dr. Santarelli said.

The diagnostic technique used in the trial to measure CSF amyloid is experimental and has yet to reach the market, Dr. Santarelli noted.

He stressed that the Roche approach involves both the more traditional clinical (observational) measurement of the patients’ symptoms and, with this new measurement technique, a molecular measurement.

Roche's “culture of combining diagnostics and therapeutics” will definitely provide useful for the development of HD drugs, Dr. Santarelli observed.

A number of other HD research efforts also focus on the search for molecular measurements.

Patient involvement

Because of the highly experimental nature of the brain shuttle and the newness of Roche’s neurological diagnostics, Dr. Santarelli could not forecast when these approaches will bear fruit in HD research.

“We have to go through all the experimentation,” he said of the partnership with Isis.

Whatever the timeline, Roche will depend on collaboration with the HD community, as it has with advocates for other diseases.

“You guys are playing an extremely important role for lowering barriers to making progress in this area,” he said. “I feel personally honored that I can make a contribution in this area.”

Quickening the pace towards a Huntington’s disease gene-silencing clinical trial: pharma giant Roche, Isis enter partnership

With an infusion of $30 million and access to new technology from the Swiss pharmaceutical giant Roche, Carlsbad, CA-based Isis Pharmaceuticals, Inc., hopes to shorten the timetable for a clinical trial of a potential breakthrough drug for Huntington’s disease. It would attack the disease at its genetic roots and could serve as a preventive medicine.

The partnership, announced April 8, puts Isis in a position “to move very aggressively to getting the drug into clinical trials,” Frank Bennett, Ph.D., the Isis senior vice president for research, said in a phone interview. “It should accelerate the program.”

The deal, which could bring Isis up to $362 million in payments for developing and licensing the drug plus royalties on sales should it prove successful, provides a key piece of the puzzle for the company’s HD program. As a dynamic mid-sized company focused on drug discovery but lacking the capital and infrastructure for large-scale clinical trials and drug commercialization, Isis has finally secured the partner necessary for bringing the potential HD drug to market.

“This is the best news,” said Don Cleveland, Ph.D., an Isis collaborator who helped envision the treatment of HD with the company’s gene-silencing antisense oligonucleotides (ASOs). “Running a clinical trial takes substantial dollars. Isis is a smaller company. Roche is one of the world’s largest and most successful pharmaceutical companies.”

The partnership gives Isis the “confidence” necessary to move from the early to later stages of the clinical trials, Dr. Bennett said. Roche, with its long experience in central nervous system drugs such as Valium, in use since the early 1960s, will not be “dropping the ball as a partner,” he added.

Dr. Frank Bennett (photo by Dr. Ed Wild)

                                                                                                                       

In line with earlier projections, Dr. Bennett stated that Isis still hopes to begin the clinical trial during the first half of 2014.

Shuttling drugs into the brain

The ASOs diminish the production of the huntingtin protein by eliminating huntingtin RNA in brain cells, which are destroyed in HD, producing motor, cognitive, and psychiatric difficulties in affected individuals. (Click here to read more about the efforts to design the drug and bring it to trial.)

Isis and Roche will experiment with the latter’s “brain shuttle” technology, which, if successful, would allow greater penetration of the drug into the brain and make it far easier for patients to take.

Isis first aimed to implant a pump in a patient’s abdomen and inject the drug directly into the brain. Then it moved to an injection into the cerebral spinal fluid (CSF) through a quarter-sized port implanted near the rib cage, with a catheter running to the area of the spinal cord.

However, as Dr. Bennett explained, with the brain shuttle technique, patients would simply need a subcutaneous injection (under the skin) similar to the kind taken by diabetes patients.

The brain shuttle would “allow us to use systemic dosing,” Dr. Bennett explained. (Systemic dosing means the drug enters the bloodstream and is thus more available in the body in comparison with an injection into the CSF.)

“It’s much more convenient,” he added. “It’s a better tolerated therapy. It could capture the symptoms earlier, maybe even prevent the development of the disease.”

Glimpsing the Holy Grail?

That convenience also makes it easier to administer the drug to gene-positive asymptomatic individuals, Dr. Bennett noted.

For ethical and scientific reasons, people in this group (including me) have rarely, if ever, participated in HD clinical trials. Basically, scientists haven’t yet figured out how to measure how a drug could benefit this group. In addition, its risk-benefit ratio is higher than it is for people with symptoms. Solving these problems, and thus completely preventing HD (as well as other neurological diseases such as Alzheimer’s), is what I have called the Holy Grail of the research community.

For the first time, the Isis-Roche partnership suggests how the grail might be found. With reduced risks, participation in trials becomes more attractive, and ethical barriers diminish. In addition, the very entry of asymptomatic people into a trial permits the collection of data about efficacy specific to that group.

However, Dr. Bennett cautioned that this approach would most likely be reserved for second-generation clinical trials. Until the initial trials are completed, it’s impossible to venture a guess about the timetable for a second generation.

“As a scientist, you can always make something better, but you have to be careful,” he said of the time needed to develop the brain shuttle for ASOs. “For a patient that’s suffering from the disease, you don’t want to over-engineer and delay getting it to the patient.”

Dr. Cleveland pointed out that the brain shuttle approach is new and has yet to be proven as a way to transport drugs into the brain.

“That’s precisely why you want to have partners like Roche,” he said. “They’ve been delivering things to the central nervous system for a long time. There’s tremendous promise. The challenge will be to bring that promise into real fruition.”

Isis and Roche will conduct joint research to discover whether they can attach the ASO to molecules that naturally shuttle other, necessary molecules into the brain across the blood brain barrier, which shields the brain from foreign substances that might cause harm and prevents the ASOs on their own from entering.

Key details and collaborators

“Huntington’s is a severely debilitating neurodegenerative disease and a large unmet medical need,” Luca Santarelli, Head of Neuroscience and Small Molecules Research at Roche, stated in the press release announcing the partnership. “Treatments are urgently needed, and we believe that the Isis approach in combination with Roche’s brain shuttle represents one of the most advanced programs targeting the cause of HD with the aim of slowing down or halting the progression of this disease.”

Under the deal, the $30 million investment from Roche will underwrite the project through Phase IIA of the three phases of the first-round clinical trial, with Isis retaining control of the project, Dr. Bennett said. If Phase IIA proves successful, Roche would conduct the more extensive Phase III trial, seek regulatory approval for the drug, and market it.

The agreement also stipulates that over time Isis will reimburse the CHDI Foundation, Inc., the multi-million-dollar non-profit virtual biotech firm that funded and advised the HD research at both Isis and Dr. Cleveland’s lab at the Ludwig Institute for Cancer Research at the University of California, San Diego. CHDI will initially receive $1.5 million, with additional reimbursements occurring as Isis receives project milestone payments from Roche. CHDI will continue to advise Isis and Roche on HD research.

“This is an exciting development for the HD community, and a testament to the excellent work that Isis has done to develop their oligonucleotide therapeutic for HD,” said Robi Blumenstein, the president of CHDI Management, Inc., the firm that carries out the goals of the CHDI Foundation. “It's very encouraging that Roche, a pharmaceutical company with a great track record in central nervous system disorders, has now entered into developing treatments for HD. CHDI looks forward to working with both companies to steer this novel approach to the clinic as soon as possible."

Isis, Dr. Cleveland, and CHDI are currently conducting a large experiment to find HD biomarkers (signs of disease) that will enable them to determine the proper dose of the ASO drug and to measure its impact during the clinical trial.

David Corey, Ph.D., of the University of Texas Southwestern also collaborated with Isis on the gene-silencing project.

(Next time: my personal thoughts on the Isis-Roche project as a powerful new sign of hope for the HD community.)

California stem cell agency approves $19 million clinical trial project as Huntington’s disease families ‘change the course of science’

Adult stem cells designed to rescue brain cells from death in Huntington’s disease patients could enter human testing in the next three to four years, thanks to a $19 million grant to an HD research team at the University of California, Davis (UC Davis), from the California Institute for Regenerative Medicine (CIRM).

If successful, this first-ever stem cell clinical trial for Huntington’s could pave the way for a possible treatment of the devastating disorder.

At a public meeting July 26, the oversight board of the $3 billion stem cell agency announced the award to the lab of researcher Jan Nolta, Ph.D., a recognized specialist in mesenchymal (pronounced “meh-zen-KI-mal”) stem cells (MSC), and her collaborator Vicki Wheelock, M.D., a neurologist and the director of the Huntington’s Disease Society of America’s Center for Excellence for Family Services and Research at UC Davis.

Dr. Nolta aims to introduce MSCs, which act as natural “paramedics” in the body, into the brains of symptomatic HD patients to test for safety and tolerability. The trial doses will be made from a sample of MSCs extracted from a healthy donor.

MSCs produce a so-called “fertilizer for the brain” (BDNF, brain-derived neurotrophic factor), whose levels plummet drastically when someone has HD. Dr. Nolta and her team have engineered MSCs to produce higher levels of BDNF in an attempt to help HD-damaged neurons recover and avoid death, thus slowing, halting, or perhaps even reversing the course of HD.

Dr. Nolta’s collaborator Gary Dunbar, Ph.D., of Central Michigan University, has already demonstrated that these MSCs mostly stop symptoms in transgenic mice that have been given the abnormal HD gene.

Dr. Jan Nolta (above) at the HD work bench at the Institute for Regenerative Cures. Below, Dr. Vicki Wheelock (photos by Gene Veritas).

The Nolta-Wheelock grant was one of eight CIRM grants totaling $151 million to labs seeking treatments for debilitating or fatal diseases, including Lou Gehrig’s disease, cancer, heart disease, and spinal cord injuries. The awards were the second largest research round in CIRM history. In 2009 the agency granted more than $200 million to researchers.

With a score of 87/100, the Nolta-Wheelock grant ranked highest in the state.

“We’re just so glad that we didn’t let the community down,” Dr. Nolta told HD activist Melissa Biliardi on The HD View internet radio program on July 23 in anticipation of the expected award.

In this same round UC Davis received two other grants – to seek treatments for peripheral artery disease and osteoporosis – that Dr. Nolta will help oversee in her role as the director of the UC Davis stem cell program and the university’s Institute for Regenerative Cures (IRC), which has nearly 150 affiliated faculty researchers.

“People are hopeful, truly hopeful for the first time,” Judy Roberson, the former president of the Northern California Chapter of the Huntington’s Disease Society of America (HDSA) and the widow of an HD victim, said after the CIRM announcement. “This is a nightmarish, cruel disease in every way but now, thanks to CIRM, we are turning the dream of a stem cell therapy trial into a reality. Research means hope for people with this disease, but research costs money. CIRM has given us all hope.”

The trial’s proposed timeline

CIRM will grant the $19 million over four years, the proposed timeline of the clinical trial project. Most of the money will cover charges such as surgeries, operating room and hospital costs, MRI scans, and other items related to the actual trial.

According to the proposal, the UC Davis team will spend the first year testing the safety of MSCs in healthy non-human primates. This stage of the project will help the team secure the necessary approval for human testing from the U.S. Food and Drug Administration (FDA), which regulates clinical trials.

In the project’s second year the team hopes to enroll at least 26 early-stage HD patients in an observational study, including motor and psychiatric tests and MRI brain scans, to obtain basic measurements of their health for comparison with readings to be taken during the clinical trial.

At the start of the third year, if all regulatory approvals have been obtained as planned, the patients will receive a single, direct injection of the MSCs into each side of their brains (a bilateral intrastriatal injection). A special neurosurgical team, which will include experts from the University of California, San Francisco, will bore a tiny hole into the skull to insert a tiny cathether to deliver the cells. Direct insertion is necessary because of the blood/brain barrier, which allows few medications to enter the brain. Patients will have part of their heads shaved. However, their hair should grow back, and the holes will heal over.

Half of the patients will receive MSCs with the extra BDNF-producing capability, while the other half will receive a placebo, MSCs without that capability.

Trial participants will receive dosages in groups and on a staggered schedule, with each successive group receiving a higher amount of the MSCs.

The remainder of the trial will primarily check for the safety of the MSCs. As a secondary goal, the scientists and physicians will also look for alleviation of symptoms and evidence that the MSCs are improving the health of the brain.

This first step in the trial is known as Phase I. If the MSCs prove safe, the team would seek funding for Phases II and III to fully measure the cells’ efficacy.

All of these plans must receive formal approval from UC Davis’s internal review board and then the FDA, after which full details will become available for potential trial participants.

A brief history of stem cells

To understand Dr. Nolta’s work we must travel back in time to explore the roots of today’s revolution in stem cell research.

Stem cells became a hot topic in the first decade of the 21st century because of the controversy over one type: embryonic stem cells. However, stem cell research long predates this controversy.

Recall that a stem cell has a very important property: it can make cells that eventually become another type of cell such as a muscle cell, skin cell, or brain cell (neuron).

Stem cells help our bodies regenerate lost or worn tissue and components such as our blood, liver, and skin.

Humans have understood the idea of regeneration since ancient times, and scientists first started discussing the concept of stem cells in the mid-1800s. Scientists first discovered stem cells in mice bone marrow in the early 1960s.

The very first stem cell therapy (treatment) in humans took place in 1968 with the successful bone marrow transplant for a leukemia patient whose marrow donor was an identical twin. This type of transplant helps the patient because bone marrow contains stem cells that produce new blood cells. Because of stem cell research, other kinds of transplantation and tissue regeneration have become possible.

Over the last few decades, scientists have identified other types of stem cells, including those that produce neurons. Stem cell research is now burgeoning around the world. Scientists use stem cells both to understand human biology and to seek therapies for diseases and traumas.

In August 2001, President George W. Bush stopped federal funding for new embryonic stem cell research because of his belief, shared by a good number of Americans, that such research destroyed human life (the embryo from which the stem cells were taken) and was therefore immoral. In California Bush’s restrictions spurred a successful movement to pass a 2004 ballot initiative, Proposition 71, that skirted the president’s order with state-level funding, created CIRM, and catapulted the state into global leadership in stem cell research.

In recent years, however, new discoveries have lessened the controversy about stem cells. Scientists have made many advances using adult stem cells – those extracted from a living human being without any risk. In 2006 researchers achieved another milestone that reduced the need for embryonic stem cells: they could now take cells from the skin or other parts of the body and reprogram them into a stem cell.

Dr. Alvin King of the University of California, Irvine, displays a neural stem cell on the screen of a microscope (photo by Gene Veritas).

The MSCs, Dr. Nolta’s focus for the past 25 years, are adult stem cells. Everyone has MSCs. They are found in the bone marrow, as well as in fat, dental tissue, and the umbilical cord. They can make bone, tendons, ligaments, and other connective tissues. MSCs grow well in lab conditions, making them a prime candidate for research.

Along with other scientists, in recent years Dr. Nolta and Leslie Thompson, Ph.D., of the University of California, Irvine, another CIRM grantee, began employing stem cells in Huntington’s research. Besides MSCs, HD researchers use human embryonic stem cells, human induced pluripotent stem cells, neural stem cells, and others.

In Dr. Nolta’s assessment, MSCs appear to have especially great potential in treating HD because of their abilities as the body’s “paramedics.” This potential is described in detail below.

From child scientist to MSC expert

Dr. Nolta’s path to the potentially historic MSC HD clinical trial began in childhood and took shape in the midst of the stem cell revolution.

“I think I was probably born a scientist,” she told me during a May 2011 visit to her lab on the occasion of the HDSA Northern California Chapter’s annual convention. “I was the kid that was out in the yard investigating bugs and watching eggs hatch and feeding baby animals that were rescued and trying to understand how caterpillars went through the chrysalis form and came out as moths and butterflies.”

Raised by a single working mom in the small northern California town of Willows and depending on grants and waitressing for her college education, Dr. Nolta received a degree in biology from Sacramento State University in 1984.

After graduation Dr. Nolta took M.A.-level science courses at UC Davis and volunteered in a lab. “We could take stem cells from the bone marrow and culture them,” she recalled. “There was this ‘magical’ potion that we could put them in and culture them for just a few days and could watch them divide and grow into blood cells. I wanted to secretly keep the cultures growing and study them.

“Where I fell in love with mesenchymal stem cells was in 1987. We started doing long-term bone marrow cultures, and there’s a component that grows out when you take a marrow aspirate from a human being that’s a mono-layer of broad, flat cells.  We used to call those the marrow-stromal cells. They later got renamed to mesenchymal stem cells due to their potentiality and all that they can do.”

Dr. Nolta learned that MSCs could assist greatly in gene therapy. Also known as cellular therapy, gene therapy involves the use or alteration of genes to treat disease. Dr. Nolta was impressed with MSCs’ strong ability to assimilate and deliver gene therapy products.

“I realized very quickly that we could engineer them to even better support the other cells in the body,” she explained.

To deepen her knowledge of stem cells and MSCs, Dr. Nolta enrolled in the Ph.D. program in molecular microbiology at the University of Southern California under the mentorship of Dr. Donald Kohn, a specialist in pediatric bone marrow transplantation. At Children’s Hospital Los Angeles she assisted in his pioneering work on bubble baby syndrome, AIDS, and other conditions.

From this experience Dr. Nolta learned the techniques of gene therapy, growing stem cells, and applying stem cell therapies in the clinic. With Dr. Kohn’s team, she performed the first cord blood gene therapy trial for infants born with bubble baby syndrome, a type of serious immune deficiency.

In 2002 the Washington University School of Medicine in St. Louis, one of the nation’s top medical schools, recruited Dr. Nolta to help build its programs in gene therapy and stem cell research. There she continued her work on gene therapy and MSCs and collaborated with her close colleague Gerhard Bauer, Ph.D., in the establishment of a GMP (good manufacturing practice) facility, a highly advanced lab crucial for producing cell and gene therapies.

The power of grassroots advocacy

However, the future of stem cell research lay in California. In 2007 UC Davis lured Dr. Nolta back to her home state to direct its stem cell programs under the umbrella of the brand-new IRC, the Institute for Regenerative Cures. CIRM awarded UC Davis $21 million to construct the IRC and its state-of-the art GMP facility. UC Davis contributed $40 million to the project.

With little knowledge of Huntington’s disease, Dr. Nolta had no plans to include it in her research program at the IRC when she was recruited.

Around the state, however, HD advocates were telling their stories of the desperate need for treatments at the public hearings of the CIRM oversight board. They pushed hard for the CIRM to back HD research.

UC Davis stem cell program manager Geralyn Annett (left), HD patient Sharon Shaffer, Alexa Shaffer,  and Dr. Nolta advocating for HD research at a CIRM board meeting at UC San Diego in 2008 (photo by Gene Veritas)

During her recruitment trip to UC Davis, Dr. Nolta met Dr. Wheelock of the HDSA Center of Excellence.

“Have you ever considered using stem cells to treat Huntington’s disease?” asked Dr. Wheelock as she rode with Dr. Nolta in an elevator.

“You know, for the last 20 years, I have been researching how to use stem cells to treat every part of the body except the brain,” Dr. Nolta responded, citing the critical hurdle of the blood/brain barrier.

“The families impacted by Huntington’s disease are truly remarkable,” Dr. Wheelock rejoined. “I’d love to introduce you to them.”

That conversation spurred Dr. Nolta to take a scientific interest in HD. More importantly, meeting the families deeply moved her. She decided to act.

With initial financial backing from HD advocates from the Sacramento area and elsewhere, Dr. Nolta delved into a project to find a way to use MSCs to combat HD.

Dr. Nolta used her early findings to apply for a grant from CIRM. In 2009 the agency awarded her lab $2.7 million to study the use of genetically reengineered MSCs to block HD at its genetic roots, first in lab dishes, then in mice (explained below).

During our interview at the IRC, Dr. Nolta pointed to the photographs of HD advocates on her desk.

“They change the course of what scientists do,” she said, breaking into tears. “My life was forever changed.”

In all, local fundraising efforts have provided some $100,000 for Dr. Nolta’s work. Donations have included $15,000 from the Deshalamar foundation and $40,000 from Team KJ, an Illinois initiative in support of Kara Jean Fleming, a 40-year-old HD patient. The Joseph P. Roberson Foundation, named for the deceased husband of Judy Roberson, has also supported Dr. Nolta’s work. Many other donors, large and small, have also contributed.

Watching the paramedics in action

With the new $19 million CIRM grant – the largest in Dr. Nolta’s career – she and the UC Davis hope to set their MSC research on the path to a treatment.

The MSCs’ many attributes make them attractive for treating HD.

“They’re very social,” Dr. Nolta explained as she played a highly magnified video in which the MSCs appeared to swim and greet one another like people playing in a swimming pool. “They like to interact with other cells.”

The MSCs also move around the body with great facility, Dr. Nolta added. They can project little tubes, called nanotubules, that tunnel into cells and inject them with necessary items such as proteins and mitochondria, the powerhouses of the cell.

“It’s like giving a cell new batteries,” Dr. Nolta explained. “They just open up a nanotubule and put the new component into the other cell. So that’s why we call them paramedics. It’s like they’re going around with tool kits to repair the other cells…. They like to check out other cells, to see if they’re healthy. They can change what they produce from what they sense from the environment and from the other cells. They just become like little factories.”

“They almost look like living organisms,” I observed.

“They are,” Dr. Nolta said. “They’re alive.”


(Watch the video below to see the MSCs in action.)

Mesenchymal Stem Cells in Action (narrated by Dr. Jan Nolta) from Gene Veritas on Vimeo.

The MSCs’ sociability results in part from the fact that damaged or sick cells and neurons put out “distress signals” that spur the paramedics into action, Dr. Nolta continued.

The same process occurs in the brain, she added. In mice that carry the human Huntington’s gene and have HD-like symptoms, MSCs injected into their brains migrated to the areas of damage.

Transplantations of human tissue often trigger a rejection by the immune systems of the recipients, requiring them to take anti-rejection drugs sometimes for the rest of their lives. This does not occur with MSCs, Dr. Nolta said.

“That’s the beauty of them,” she said. “They’re transplanted from one patient to the next with really no regard to tissue matching. They actually shelter themselves from the immune system through some of the things that they secrete. We think that’s part of their natural function in the body.

“When there’s a wound or a heart attack or some kind of ischemic event, a stroke, they can go to that area, and they want to cause the tissue to heal without scarring. That’s part of their innate mission. They don’t want the immune system to see it while it’s getting fixed up, because you could start making auto-antibodies to that damaged tissue, and then you would destroy that tissue. We think that the MSC just go to the scene of the injury and keep the immune system at bay while they’re doing their remodeling. It’s kind of like keeping everybody out of a construction site.”

The goal: restoring neurons and connections

According to Dr. Nolta, the MSCs secrete substances that help restore the vital connections between neurons. Such connections are lost in HD. Additionally, in secreting BDNF and other brain growth factors, the MSCs can help damaged neurons recover. She likened this scenario to a chain of Christmas lights that, missing a bulb, will go out. Restoring the bulb – a healthy neuron – gets the whole chain working again.

In the case of the proposed clinical trial, the UC Davis team will ramp up the MSCs’ capability to provide BDNF. In mice tests, they have increased that capability by a hundredfold.

The big question, Dr. Nolta told me in an interview on July 30, 2012, is this: how effective will MSCs prove in helping the entire striatum, an area of the brain deeply compromised by HD and where the MSCs will be injected?

“The MSCs can secrete huge amounts of BDNF, so that might be effective” in helping to restore the striatum, she said.

Attacking HD’s genetic roots

If the MSC BDNF trial proves successful, the UC Davis team could use another up-and-coming tool for combatting HD: RNA interference.

In designing a substance known as a small interference RNA molecule (siRNA), other researchers have already reducedthe amount of harmful huntingtin protein in the brains of test animals. A similar approach, known as antisense, has demonstrated similar results.  Both approaches should enter clinical trials within the next few years, if not sooner.

Still in the early stages of this aspect of their research, Dr. Nolta and her UC Davis HD team have discovered a way to deliver siRNA into cells in a dish using MSCs.

Some researchers are examining ways to implant new neurons or fetal-striatal stem cells into patients’ brains to repair the damage caused by HD. However, Dr. Nolta pointed out that those cells could become affected by HD.

The use of siRNA could protect those and other cells from HD. Dr. Nolta has photos and video of the MSC nanotubules transferring siRNA into other cells. Her lab is now testing MSC siRNA in mice.

Controlling the huntingtin gene and protein effectively is the “holy grail” of HD research because it would allow gene-positive, non-symptomatic people like me to take a preventative treatment.

‘A super, super clean place’

Although the human brain has MSCs, in HD people those MSCs make the same mutant huntingtin as the other cells in the brain and, indeed, in the rest of the body. Compromised in this manner, the MSCs in HD people’s brains cannot make necessary levels of BDNF.

As a result, for the Phase I MSC BDNF trial, the HD team will make batches of MSCs from bone marrow cells provided by a healthy donor and therefore containing normal, non-disease-causing huntingtin.

Federal regulations require GMP for any substance that will be tested in humans. Thus, in the run-up to Phase I, the MSC batches will be made at the UC Davis Institute for Regenerative Cure’s GMP facility. It could make enough MSCs for 100 patients, Dr. Nolta said.

“You need your own facility to get up to this scale,” she commented. “How to manufacture these batches of cells is a whole industry in and of itself. It’s usually companies that would do this. Sometimes they charge exorbitant fees.”

This level of “scale-up” to a clinical trial is “our forte here,” Dr. Nolta told me in our recent interview. The National Institutes of Health and insurance companies don’t fund these kinds of initiatives, she noted, leading many drug candidates with good potential to “fall into the valley of death.”

During my visit to the IRC, she referred to the GMP as a “super, super clean place.” It will triple-check the quality of the MSCs.

As explained to me by GMP specialist Bill Gruenloh, normal air contains hundreds of millions of particles per cubic foot. Air handlers and HEPA filters reduce the number of particles in the manufacturing room to only 10,000. Areas under tissue culture hoods have just 100. In addition, the highly specialized GMP employees maintain meticulous records of every article in the facility. A computer constantly monitors the GMP, and the employees double-check readings with hand-held instruments. Thus no micro-organisms are present in critical areas of the GMP.

If a contamination or other problem occurs with a test drug, the GMP records help trace the cause, Gruenloh said. 

UC Davis GMP specialist John Walker at work (photo by Gene Veritas)

The GMP also stores stem cells and other items at carefully controlled, very low temperatures. The UC Davis GMP developed the first GMP-grade cell-sorter in the world, Gruenloh added.

In addition, the GMP houses its own quality control lab to check the safety of products and verify that they are free of contaminants and bacteria.

Putting the project in perspective

As Dr. Nolta has pointed out on several occasions, more than 10,000 patients worldwide have already received MSCs infused into the blood stream. In fact, the drug regulatory agencies of Canada and New Zealand have already approved the use of MSCs to be prescribed as a drug to treat certain diseases, although not yet HD. In addition, at least four companies are currently testing MSCs or MSC-like cells in clinical trials for other neurodegenerative conditions.

As always, we need to recall that only 10 percent of clinical trials ever lead to an actual drug. Mathematically speaking, the odds are stacked against the Nolta-Wheelock project.

Even if the Phase I trial proves a dramatic success, the UC Davis team will need to find ways to fund Phases II and III, which will require larger numbers of participants and thus cost more money. Backed by public bonds, CIRM will run out of money in about four years, unless the agency can attract private investors. At least for now, the state of California’s dire fiscal situation makes further public funding unlikely, although one cannot predict the mood of the voters.

With an eye to the future, Dr. Nolta and UC Davis have secured a patent for the MSC siRNA delivery technology in the hopes that a pharmaceutical firm or other private investor might risk supporting further research and testing in exchange for some of the potential profits from a drug. She noted that companies visit the IRC regularly, although none has yet expressed an interest in supporting HD work.

Despite these caveats, I am struck by the apparent simplicity of the UC Davis approach: using human cells as a way to deliver remedies to the brain.

I am also impressed with the UC Davis team’s boldness in moving as quickly as possible towards a clinical trial. In fact, some scientists think they’re moving too quickly with their siRNA plans, although Dr. Nolta characterized their criticism as a “misunderstanding” of her project, since it is the BDNF trial, not the siRNA, that is moving toward the clinic first. The siRNA studies are only in early rodent testing.

A successful MSC HD trial would extend immense hope to patients suffering from other neurological diseases (such as Alzheimer’s and Parkinson’s), as well as ischemia, heart disease, and other conditions, Dr. Nolta said. Such hope would likely translate into greater private funding for MSC research.

Hope, realism, and future advocacy

California’s HD stem cell advocates – along with fellow HD activists around the world – can feel confident that CIRM is having an important impact on HD research.

We now await the MSC trial results – and with great hope!

However, we should also proceed with patience and realism.

Science takes time.

Furthermore, most scientists think that treating HD successfully will require a cocktail of remedies, not just one.

With grassroots support for, and intense interest in, the UC Davis HD program, the HD community is betting heavily that MSCs will provide a way to alleviate the conditions’ horrific symptoms.

Judging from the unprecedented excitement about the CIRM grant that I have witnessed in the HD Facebook community in comparison with news about other breakthroughs, I think people perceive stem cells as providing the greatest hope. Indeed, for many Americans, stem cells seem to hold an almost magical appeal, as they once did for the young Jan Nolta at the start of her career. People seem to sense viscerally that they can provide cures and replace lost cells and tissues. Could stem cells represent our new Fountain of Youth?

Naturally, we all want, need, and deserve to celebrate the CIRM award.

I myself have advocated for California stem cell research for more than a decade through HDSA-San Diego. Having lost my mother to HD in 2006 at the age of 68 and tested positive for HD in 1999, I anxiously await treatments. When people told me that potential stem cell breakthroughs lay too far in the future to offer me hope, my resolve to fight only strengthened.

Yet we should also keep in mind that scientists are working just as hard on numerous other, highly important approaches. They don’t stir the controversy and publicity that have surrounded stem cells, and many are extremely difficult to understand, but they could very well lead to effective treatments.

In effect, the Nolta-Wheelock project is another “shot on goal” in the search for HD treatments. The CHDI Foundation,Inc., the major private backer of HD drug research, and its collaborators will attempt as many as eight such shots in the next few years. The more shots, the better the chances of finding treatments and a cocktail.

In the meantime, just as Dr. Nolta, the UC Davis team, and scientists around the world work feverishly to liberate us from HD, we in the HD community must continue to strategically advocate for our cause, creatively help change the course of science, and participate in the crucial research studies and clinical trials that provide the key to defeating HD.

* * *

Additional information

Once the UC Davis trial is approved the FDA, details of how to participate will become available at www.clinicaltrials.gov.

For an HD family member’s account of the historic CIRM meeting, read Katie Jackson’s report at The Huntington’s Post.

To learn more about Dr. Nolta’s research, read an article by Dr. Marsha Miller by clicking here.

For the official CIRM evaluation of the project, please click here.

For in-depth reporting on CIRM’s activities, see California Stem Cell Report.

You can also read an impassioned defense of stem cell research by global HD advocate Charles Sabine.

HD scientist Dr. Elena Cattaneo provides an update on the European Union’s support for stem cell research.

For an overview of stem cells, see Stem Cells for Dummies.

On stem cells and HD, also see www.HDBuzz.net.

To see a presentation by Dr. Nolta on MSCs and HD, watch the video below.

Towards Stem-Cell Treatments for Huntington's Disease: Talk by Dr. Jan Nolta from Gene Veritas on Vimeo.