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Deadly Progression of ALS Reversed in an Amazing Stem Cell First
Last May, 39-year-old Ted Harada was diagnosed with ALS, also known as Lou Gehrig's disease. It's one of the worst diagnoses anyone could get.
He and his doctors expected his health to have severely declined by now. But thanks to an experimental stem cell treatment, he has tossed his cane and is once again playing in the pool with his three kids.
"Every day is a good day for me right now," Harada told me. "I've made some quantum leaps after the surgery and... I'm maintaining the drastic improvements I've made."
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The prognosis for ALS is likely death in fewer than three years after gradually losing your ability to move, speak and breathe. Harada got exactly that horrible news after losing strength in his left leg and feeling short of breath after just a few stairs or walking to the mailbox. His hands became too weak to open a Ziploc bag.
Then his neurologist told him about an experiment at Emory University that was recruiting ALS patients to test a stem cell treatment.
The surgeons told Harada that injecting the stem cells into his spine likely would not help him personally, and might even cause harm. But the study would hopefully help scientists find an effective treatment in the future. Harada had nothing to lose and expected nothing - he became study subject number 11 and underwent surgery on March 9.
It's incredibly moving to hear Harada talk about his recovery, which he knows might be temporary.
"I've always been the kind of dad to wrestle on the floor with my kids and tickle them and make them giggle, and that was going away before," Harada told me. "Now when we get in the pool and they want to play Marco Polo, I can do that."
The Emory surgeons injected 1 million neural stem cells into 10 locations in Harada's spine (earlier patients received fewer cells; the dosage was gradually increased as the trial progressed). All of the cells came from a single voluntarily aborted and donated two-month-old fetus. Using technology developed by Neuralstem, scientists multiplied the cells and created enough of them to treat all of the patients in this trial and beyond.
"We took one small part of the spinal cord and isolated one million stem cells which are now going to, we hope, treat millions of people around the world," Dr. Karl Johe, chief scientific officer at Neuralstem told me.
Going into the study, expectations were low. As a safety precaution, the FDA forced the researchers to inject only one-quarter the number of stem cells they originally planned to use. The investigators hoped to show the cells were safe to use, but anticipated little more.
Two of the 12 patients died during the trial, one after a heart attack and another because of progress of his ALS. The rest of the patients' conditions have remain unchanged.
The researchers hope the Food and Drug Administration will allow them to add six more patients to the trial so they can collect more data on the treatment's safety. Neuralstem is also awaiting approval to begin the first phase of a fetal stem cell trial in chronic spinal cord patients.
Unregulated stem cell outlets, such as the one promoted by Republican presidential candidate Rick Perry, claim success treating ALS and just about every other disease you can imagine. But they haven't gone through the painstaking methodology required to run an FDA-approved human clinical trial, which demands reams of data with the goal of assuring safety and eventually proving efficacy. Such trials can also help convince insurance agencies to cover the treatments. Otherwise, rogue outlets will continue charge up to 10s of thousands of dollars for treatments.
"We go through the FDA process, which is excruciatingly slow, but we do that because it's what the law says we have to do," Johe said.
Update: The original version of this article said the Emory and Neuralstem researchers are awaiting FDA approval for a phase two clinical trial. They are actually waiting for approval to add six more patients to their phase one trial.
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Blazing the Trail
A number of biotechnology firms dedicated to stem cells have been launched in the past few years, thanks to strong venture capital funding in geographic areas where government and science have favored stem cell research, according to Frost & Sullivan.
Notably, California ranks highest, with a total of 10 firms dedicated to all kinds of stem cell research receiving either venture or IPO-backed funding. It’s interesting to note that Geron Corp., which works with hESCs, has the maximum market capital value at $605 million, despite the fact that adult stem cell research receives more funding.
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Geron, located in Menlo Park, Calif., is considered by many to be the top biotechnology company in the field of stem cell research. Since its founding in 1990, Geron has been granted more than 260 patents. The company has two anti-cancer products in human clinical trials. In 2009, Geron received FDA approval to begin Phase I testing in humans of GRNOPC1, an eSC-based drug designed to treat specific forms of spinal cord injury through remyelination of damaged axons. Geron also has several other embryonic stem cell treatments that are still in the preclinical phase,
including GRNCM1, a treatment for heart disease, and GRNIC1, a treatment for diabetes.
Here, we feature a handful of other companies that stand out as leaders in this market, according to Frost & Sullivan.
Company: Aastrom Biosciences Inc.
Founded: 1989
Location: Ann Arbor, Mich.
Employees: 65
Focus: Developing enhanced autologous cellular therapies for the treatment of severe, chronic cardiovascular
diseases
Borrowing its name from its location—“Ann Arbor Stromal” was its first moniker—Aastrom Biosciences Inc. began as a device company but is now known as a developer of process technologies and devices for cell therapy applications, including stem cell therapies and gene therapy.
Unlike some of the other companies operating in the same space, Aastrom manufacturers the autologous cells it uses in-house. A small quantity of bone marrow is taken from a patient’s hip, and in a 12-day process, Aastrom expands the cell populations found in the extracted marrow. Then, in a single inpatient procedure, the expanded mixed-cell therapy produced from this process—called ixmyelocel-T—is administered to the same patient to promote healing of the affected tissues.
“We have designed our own highly automated, fully closed cell processing system,” explains Tim Mayleben, Aastrom’s CEO, president and director. “It is the best device in the world for processing autologous cells. And our success has been to think both strategically and medically about the kinds of diseases our particular technology is well-suited for.”
Specifically, those are critical limb ischemia and dilated cardiomyopathy—critical cardiovascular diseases that currently have limited or no treatment options. The company is in a Phase III clinical trial to study ixmyelocel-T patients with critical limb ischemia and two Phase II clinical trials to study the therapy in patients with dilated cardiomyopathy.
“These chronic, long-term, progressive diseases are well-suited to our technology,” says Mayleben. “There are literally no treatment options for these patients, and of the options that are available—amputation, heart transplant, etc.—these are limited in availability and expensive. Our vision at Aastrom is to get the first autologous cell therapy product in physicians’ hands and used by patients, so we can change the way that medicine is practiced. Our technology also has applications in other disease areas that we are just now starting to explore.”
Company: Advanced Cell Technology (ACT)
Founded: 1994
Location: Santa Monica, Calif., and Marlborough, Mass.
Employees: 32
Focus: Retinal degeneration; blood and cardiovascular diseases
Although ACT was principally focused on hESCs, the company now also has some interesting work involving induced pluripotent stem (iPS) cells. ACT has three cellular product platforms based on its stem cell technology—the first-ever proven alternative method for successful hESC generation without harm to the embryo, called the "single-cell blastomere" technique.
First, the company is focused on commercializing its hESC-based Retinal Pigment Epithelial (RPE) therapy for degenerative retinal disease, for which it recently initiated two Phase I/II clinical trials. Retinal degeneration can cause a variety of blinding diseases, including retinitis pigmentosa, Stargardt’s disease (juvenile macular degeneration), age-related macular degeneration (AMD) and other degenerative diseases of the retina.
“One of the great things about working with the eye is that you don’t have the immune rejection issues you would find in other parts of the body,” says Gary Rabin, chairman and CEO of ACT.
ACT is particularly focused on AMD, which afflicts more than 30 million people worldwide and is the leading cause of blindness in people aged 60 and older in the United States. And as average life expectancy continues to rise, it is predicted that the incidence of AMD will only continue to rise in tandem. Dry AMD, the most prevalent form of the disease, represents a $25 billion to $30 billion market in the United States and Europe alone, and there are currently no approved therapies available for this condition.
On July 14, ACT announced the dosing of the first patients in each of its two Phase I/II clinical trials for Stargardt's macular dystrophy and dry AMD using RPE cells derived from hESCs. The patients were treated by Dr. Steven Schwartz, retina division chief at UCLA's Jules Stein Eye Institute. Both patients successfully underwent the outpatient transplantation surgeries and are recovering uneventfully.
“It would be great if the end result of these clinical trials is if we arrest the decline of age-related macular degeneration,” says Rabin. “The math works out readily to see how this could be the largest drug therapy of all time—this could be bigger than Lipitor.”
ACT is also developing its hESC-based Hemangioblast (HG) platform for the treatment of blood and cardiovascular diseases in a partnership with CHA Biotech of Korea.
Finally, the company is focused on advancing its Phase II-approved Myoblast autologous adult stem cell therapy for the treatment of chronic heart failure, advanced cardiac disease, myocardial infarction and ischemia.
ACT owns or licenses more than 150 patents and patent applications related to stem cell therapy and regenerative medicine. The company also recently announced a collaboration with Roslin Cells for the storage and distribution of eSCs using ACT's Blastomere technology.
Company: Aldagen
Founded: 2002
Location: Research Triangle Park in Durham, N.C.
Employees: 16
Focus: Developing proprietary adult stem cell products for tissue repair and regeneration, particularly in the cardiovascular market
When a company decides to enter the stem cell research arena, it must make a very important decision: how and from where to derive the cells they will use. For Aldagen, a clinical-stage biopharmaceutical company developing proprietary regenerative cell therapies, that question served as the foundation for the formation of the company.
In 2002, Aldagen’s founders took technology developed at Johns Hopkins University and Duke University and started a commercial enterprise. The technology identifies, selects and isolates specific adult stem cells that express high levels of the enzyme ALDH, which plays an important role in controlling the developmental state of stem and progenitor cells. It converts vitamin A into retinoic acids, which regulate genes and influence the differentiation of blood, neural, endothelial and other types of stem and progenitor cells.
Because Aldagen uses this technology to collect autologous cells from a patient’s own bone marrow, the risk of potential rejection of the injected cells in a patient is minimalized, says Edward L. Field, the company’s chief operating officer.
“When you compare us to other companies, we have a unique cell population that no one else has,” Field says. “What we do is very different, but also very simple. We don’t manipulate, culture or expand cells, so we are able to fairly rapidly produce and deliver them to the patient.”
Compared to some of the other companies we are featuring here, Aldagen is fairly young, having operated for less than 10 years. Field attributes the company’s youth to “the fact that a lot of us are trying to do what has never been done before.”
“If you think about commercializing new technology in our industry, it usually takes 20 to 25 years from the seminal event to get commercial products to market, and stem cells are no different,” he says.
Companies like Aldagen will be able to realize the promise of this groundbreaking research “if we can achieve the next milestone in stem cell research, which is putting Phase III studies and data sets on the table,” says Field.
Aldagen is headed in that direction, as it is beginning Phase II studies involving therapeutic candidates for critical limb ischemia and ischemic heart failure. Also, in May, the company—along with its collaborator, the Los Angeles Brain and Spine Institute (LABSI)—announced the enrollment of the first subject in a clinical trial that studies ALD-401, a unique stem cell population derived from a patient’s own bone marrow, for the treatment of ischemic stroke.
“The stroke market alone presents billion-dollar market opportunities,” says Field, “because there are no therapeutic options or small-molecule drugs to treat it. In addition, our therapy is a regenerative, restorative kind of therapy that has the potential to take costs out of the healthcare system by keeping patients ambulatory. We have talked to payors, and they are very encouraging as we move this program forward.”
Company: Neuralstem Inc.
Founded: 1996
Location: Rockville, Md., and San Diego; plans to open subsidiary in China soon
Employees: 16
Focus: Using its patented neural stem cell technology to treat central nervous system diseases
In January 1992, attorney Richard Garr sat at the bedside of his four-year-old son Matt at Children’s Hospital in Washington, D.C., helplessly watching his difficult recovery after an 18-hour procedure to remove a brain tumor.
Nearly 20 years later, Garr is the president and CEO of Neuralstem Inc., a publicly traded biotherapeutics company that is making headlines for its stem cell clinical trials to treat amyotrophic lateral sclerosis, (ALS, commonly known as Lou Gehrig's disease) and depression—and eventually, other diseases of the central nervous system (CNS).
Bonded to the father of one of his son’s classmates, Dr. Karl Johe—a staff scientist at the Laboratory of Molecular Biology of the National Institute of Neurological Disease and Stroke—Garr saw an opportunity to alleviate Matt’s suffering. In 1996, he and Johe joined forces to commercialize Johe’s Human Neural Stem Cell technology.
The technology allows for the isolation of CNS stem cells from tissue; the expansion, in vitro, of each cell up to a billion-billion times, or 60 doublings; and the controlled differentiation of the cells into mature, physiologically relevant human neurons and glia that can be used to treat CNS diseases and conditions. This provides a unique window for traditional drug discovery and genomic applications, Garr says.
“We screen against ourselves, and we screen against physiologically relevant human cells, so we can really see what’s actually happening, which is predictive of what will happen in humans,” he explains.
Neuralstem has 14 patents to its name—issued all over the world—with more than 20 others pending. The company’s work with stem cells is evenly divided between using them to develop actual therapeutics and to screen against for drugs. The company currently has two Phase I clinical trials underway.
The first is evaluating the safety of Neuralstem’s spinal cord stem cells in the treatment of ALS, and notably, is the first ALS stem cell trial to be approved by the FDA. In June, Neuralstem announced that 12 patients being treated at Emory University in Atlanta safely received injections in the lumbar region of the spine, prompting the trial's Safety Monitoring Board (SMB) to unanimously approve advancing the trial to transplantations in the cervical region. Neuralstem hopes these injections can help alleviate the breathing and swallowing difficulties that often lead to death in ALS patients.
Neuralstem’s second Phase I trial is testing NSI-189, the lead compound in the company’s neuroregenerative small-molecule drug platform, for the treatment of major depression. Phase Ia is testing the drug in healthy volunteers for safety and tolerability.
Neuralstem hopes to conclude both trials within the next five years, and is preparing to do a stroke trial in China. In fact, the company has several projects in the works that will give it a significant presence in Asia as well as the United States.
“We have a fairly global ambition in terms of rolling out products and studies, and we’re growing our infrastructure in that direction,” says Garr.
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Honolulu: So Far, So Good in Stem Cell Safety Study for ALS
Injecting neural stem cells into the lumbar spinal cord is a safe procedure for people with amyotrophic lateral sclerosis, according to interim data presented at the American Academy of Neurology 63rd Annual Meeting this week in Honolulu, Hawaii. Researchers working with Neuralstem, Inc., Rockville, Maryland, presented data on the first nine people to receive the treatment, all of whom are still alive four to 15 months after the surgery. The scientists, who have performed three more surgeries since assembling the interim report, plan to continue the Phase 1 study with 18 total participants.
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Neuralstem has developed a stable line of neural stem cells from donated fetal tissue. The ALS trial is the company’s first human study; they are also planning to try the cells for spinal cord injury and stroke. The hope, said Neuralstem chief operating officer Karl Johe, is that the stem cells will prolong survival of motor neurons. “The graft will reach out, form synapses with the remaining host motor neurons, and protect them from the further ravages of the disease,” he suggested. That remains to be determined.
The trial, led by Eva Feldman of the University of Michigan combines the neural stem cell line with new surgical technology and a new method to measure ALS progression.
The researchers wanted to deliver the cells directly into the lumbar spinal cord. To prevent movement during the two minutes it takes to complete the injection, Nicholas Boulis, a neurosurgeon at Emory University, developed a device to mount the needle directly on the person’s body. “When the body moves, the whole platform moves with the body,” Johe said.
Although it is too early in this safety study of people with advanced disease to look for benefits from the treatment, the researchers are also using a new method, electrical impedance myography (see ARF related news story), to follow disease progression.
The results so far indicate that the cells cause no harm. The only adverse events were related to the surgery itself, or the immunosuppressive drugs the doctors prescribed to prevent rejection of the cells. Next, the scientists plan to pursue cervical spinal cord injections, which are riskier because any abnormal stem cell growth could push up against the spinal cord and interfere with nerve signals needed for breathing.
The trial is an important one, and the stem cells might indeed have some effect on the neurons around them, said Lucie Bruijn of the ALS Association. “With all of the stem cell studies that are being offered worldwide with so little rigor, it is exciting to see this is so carefully undertaken,” she told ARF.—Amber Dance.
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U-M stem cell trial to enter crucial phase
The first clinical trial using stem cells in Lou Gehrig's disease patients soon will begin testing the safety of the procedure in an area of the spine that eventually could be life-saving.
The landmark trial aims to slow progression of the fatal disease, also known as amyotrophic lateral sclerosis, or ALS, by injecting millions of stem cells into patients.
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Neuralstem’s new branch
After 14 years spent working on neural stem cell therapies for neurological disorders, Neuralstem Inc. thinks it has found a second way to monetize its research investment. This quarter, the company plans to begin a Phase I trial of its first small molecule therapeutic discovered using the company’s CNS stem cell lines.
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Neuralstem was founded in 1996 to develop human CNS stem cell lines to treat neurological disorders such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI). The company’s lead product, NSI-566RSC, is a human spinal cord-derived stem cell line in Phase I testing to treat ALS.
In 2000, the U.S. Department of Defense’s Defense Advanced Research Projects Agency (DARPA) awarded Neuralstem a contract to use the company’s human neural stem cell lines to screen for an orally available small molecule with activity in the hippocampus. The objective was to identify compounds that could trigger growth of hippocampal neurons to counteract the stress-induced hippocampal atrophy that is believed to cause impaired cognition and memory in soldiers.
While those screens did turn up a few small molecules that triggered neurogenesis in cultured human hippocampal neural stem cells, DARPA discontinued funding of the research following a change in priorities in the wake of the 9-11 terrorist attacks. Neuralstem set the small molecules aside and returned to moving its stem cell therapy pipeline forward.
Over time, multiple lines of evidence from animal models and patients have suggested a link between impaired growth of hippocampal neural stem cells and neuropsychiatric diseases. In particular, chronic depression has been associated with atrophy and shrinkage of the hippocampus.
Those findings, combined with the receipt of a U.S. patent covering the composition of matter and use of the small molecules to promote neurogenesis to treat CNS diseases, led Neuralstem to revisit the small molecule strategy in 2009.
Neuralstem scientists hypothesized that their small molecules might be able to stimulate growth of new neurons in the hippocampus to treat depression. To test that idea, the company chose NSI-189, the best of four small molecule nicotinamide derivatives at stimulating neurogenesis in cell culture and mice.
NSI-189 is now set to begin a two-part Phase I trial. If the safety endpoints are met in healthy volunteers, the second part will enroll depressed patients for a dose-escalation study. The entire trial is expected to last about one year, CSO and cofounder Karl Johe told BioCentury.
Meanwhile, the company will work on identifying the molecular target of NSI-189.
“Our screens are set up to identify compounds that enhance the complex cellular process of neurogenesis, which involves a variety of different neural pathways that include many different potential targets. Thus, based solely on those screens, we cannot say what the molecular target of NSI-189 is,” Johe said.
He hypothesized NSI-189 might reverse the disease process in depression by “triggering structural changes in the hippocampus, including formation of new synapses and increased hippocampal volume.”
If that proves true, Johe said, the improvements achieved with NSI-189 would probably be longer-lasting than those achieved by marketed drugs such as selective serotonin reuptake inhibitors (SSRIs), which transiently alter serotonin levels.
Johe said the small molecule approach is complementary to the company’s cell therapies.
“The small molecules would be ideal for triggering growth of endogenous stem cells to treat neuropsychiatric disorders, whereas the stem cell therapies are probably more geared toward indications like spinal cord injury,” he said. “Looking very far ahead, we might speculate that the two approaches could be used together to treat some disorders — stroke, for example.”
“Because the marketed antidepressants are orally active compounds, the invasive surgical procedures necessary for neural stem cell transplant may seem impractical to doctors and regulatory agencies for most forms of depression,” noted CEO Richard Garr.
Garr also thinks NSI-189 could be useful in Alzheimer’s disease, as enhancing neurogenesis could lead to improvements in cognition and memory. “Depending on how the depression trial goes, we hope to be able to begin a clinical trial in AD sometime in 2011,” he said.
NSI-189 is exclusively licensed from an undisclosed chemistry company that supplied some of the compound libraries originally screened under the DARPA project.
Garr said Neuralstem hopes to partner out the other small molecule nicotinamide derivatives identified by its screen, as the company’s resources are sufficient to move only NSI-189 into the clinic.
“We are also interested in partnering out our stem cell discovery platform to identify whole new classes and families of compounds that could treat CNS disorders,” he said.
According to Johe, “One area of interest might be multiple sclerosis (MS). Using our stem cell screen, it might be possible to identify compounds that promote differentiation of oligodendrocytes and myelination.”
Neuralstem plans to continue to develop and commercialize its stem cell therapy pipeline on its own, Garr said.
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FOX Medical Team
