Old brains in mice given a trait of young brains with embryonic nerve transplant

As we age our brains become less adept at making new nerve connections or repairing broken ones. A CIRM-funded team at the University of California, Irvine, restored this youthful ability, called nerve plasticity, to adult mice by transplanting embryonic nerve cells.

old to young

Specifically, they worked with mice that had a form of blurred vision known as amblyopia and the nerve cells they transplanted were ones that produce the nerve signal GABA. That amino acid helps regulate many aspects of brain function, including vision. The transplanted nerve cells allowed the brain to rewire itself and make connections that were missing and causing the poor vision. Several weeks later, the mice started to see normally.

The researchers transplanted the new cells directly into the visual cortex where the new nerve connections were needed. The mice had developed amblyopia, like humans, because the proper nerve connections failed to develop during a critical period when they were young. At the point in time that the transplanted embryonic cells would be going through that same critical period is when the researchers saw the improvement in vision for the adult mice. In a press release picked up at MedMerits.com the leader of the team, Sonil Gandhi explained what they saw:

“These experiments make clear that developmental mechanisms located within these GABA cells control the timing of the critical period.”

Gandhi added that the work should open up the possibility of trying to use GABA cell transplants to retrain the brain after injury or to repair congenital defects.

The news site NewsMax wrote an article on the research adding a bit more analysis.

A hopeful sight: therapy for vision loss cleared for clinical trial

Rosalinda Barrero

Rosalinda Barrero, has retinitis pigmentosa

Rosalinda Barrero says people often thought she was rude, or a snob, because of the way she behaved, pretending not to see them or ignoring them on the street. The truth is Rosalinda has retinitis pigmentosa (RP), a nasty disease, one that often attacks early in life and slowly destroys a person’s vision. Rosalinda’s eyes look normal but she can see almost nothing.

“I’ve lived my whole life with this. I told my daughters [as a child] I didn’t like to go Trick or Treating at Halloween because I couldn’t see. I’d trip; I’d loose my candy. I just wanted to stay home.”

Rosalinda says she desperately wants a treatment:

“Because I’m a mom and I would be so much a better mom if I could see. I could drive my daughters around. I want to do my part as a mom.”

Now a promising therapy for RP, funded by the stem cell agency, has been cleared by the Food and Drug Administration (FDA) to start a clinical trial in people.

The therapy was developed by Dr. Henry Klassen at the University of California, Irvine (UCI). RP is a relatively rare, inherited condition in which the light-sensitive cells at the back of the retina, cells that are essential for vision, slowly and progressively degenerate. Eventually it can result in blindness. There is no cure and no effective long-term treatment.

Dr. Klassen’s team will inject patients with stem cells, known as retinal progenitors, to help replace those cells destroyed by the disease and hopefully to save those not yet damaged.

In a news release about the therapy Dr. Klassen said the main goal of this small Phase I trial will be to make sure this approach is safe:

“This milestone is a very important one for our project. It signals a turning point, marking the beginning of the clinical phase of development, and we are all very excited about this project.”

Jonathan Thomas, the Chair of our Board, says that CIRM has invested almost $20 million to help support this work through early stage research and now, into the clinic.

“One of the goals of the agency is to provide the support that promising therapies need to progress and ultimately to get into clinical trials in patients. RP affects about 1.5 million people worldwide and is the leading cause of inherited blindness in the developed world. Having an effective treatment for it would transform people’s lives in extraordinary ways.”

Dr. Klassen says without that support it is doubtful that this work would have progressed as quickly as it has. And the support doesn’t just involve money:

“CIRM has played a critical and essential role in this project. While the funding is extremely important, CIRM also tutors and guides its grantees in the many aspects of translational development at every step of the way, and this accelerates during the later pre-clinical phase where much is at stake.”

This is now the 12th project that we are funding that has been approved by the FDA for clinical trials. It’s cause for optimism, but cautious optimism. These are small scale, early phase trials that in many cases are the first time these therapies have been tested in people. They look promising in the lab. Now it’s time to see if they are equally promising in people.

Considering we didn’t really start funding research until 2007 we have come a long way in a short time. Clearly we still have a long way to go. But the news that Dr. Klassen’s work has been given the go-ahead to take the next, big step, is a hopeful sign for Rosalinda and others with RP that we are at least heading in the right direction.

One of our recent Spotlight on Disease videos features Dr. Klassen and Rosalinda Barrero talking about RP.

This work will be one of the clinical trials being tested in our new Alpha Stem Cell Clinic Network. You can read more about that network here.

Scientists Sink their Teeth into Stem Cell Evolution

Sometimes, answers to biology’s most important questions can be found in the most unexpected of places.

As reported in the most recent issue of the journal Cell Reports, researchers at the University of California, San Francisco (UCSF) and the University of Helsinki describe how studying fossilized rodent teeth has helped them inch closer to grasping the origins of a particular type of stem cell.

Rodents' ever-growing teeth hold clues to the evolution of stem cells, according to a new study.

Rodents’ ever-growing teeth hold clues to the evolution of stem cells, according to a new study.

Understanding the microenvironment that surrounds each stem cell, known as a stem cell niche, is key to grasping the key mechanisms that drive stem cell growth. But as UCSF scientist Ophir Klein explained, many aspects remain a mystery.

“Despite significant recent strides in the field of stem cell biology, the evolutionary mechanisms that give rise to novel stem cell niches remain essentially unexplored,” said Klein, who served as the study’s senior author. “In this study, we have addressed this central question in the fields of evolutionary and developmental biology.”

In this study, Klein and his team focused on the teeth of extinct rodent species. Why? Because many species of rodent—both extinct species and those alive today—have what’s called ‘ever-growing teeth.’

Unlike most mammals, including we humans, the teeth of some rodent species continue to grow as adults—with the help of stem cell ‘reservoir’ hidden inside the root.

And by analyzing the fossilized teeth of extinct rodent species, the researchers could gain some initial insight into how these reservoirs—which were essentially a type of stem cell niche—evolved.

Most stem cell niche studies take cell samples from hair, blood or other live tissue. Teeth, as it turns out, are the only stem cell niches that can be found in fossil form.

In fact, teeth are “the only proxy…for stem cell behavior in the fossil record,” says Klein.

After analyzing more than 3,000 North American rodent fossils that varied in age between 2 and 50 million years ago, the researchers began to notice a trend. The earlier fossils showed short molar teeth. But over the next few million years, the molars began to increase in length. Interestingly, this coincided with the cooling of the climate during the Cenozoic Period. The types of food available in this cooler, drier climate likely became tougher and more abrasive—leading to evolutionary pressures that selected for longer teeth. By 5 million years ago, three-quarters of all species studied had developed the capability for ever-growing teeth.

The team’s models suggest that this trend has little chance of slowing down, and predicts that more than 80% of rodents will adopt the trait of ever-growing teeth.

The next step, says Klein, is to understand the genetic mechanism that is behind the evolutionary change. He and his team, including the study’s first author Vagan Tapaltsyan, will study mice to test the link between the genetics of tooth height and the appearance of stem cell reservoirs.

Brain’s Own Activity Can Fuel Growth of Deadly Brain Tumors, CIRM-Funded Study Finds

Not all brain tumors are created equal—some are far more deadly than others. Among the most deadly is a type of tumor called high-grade glioma or HGG. Most distressingly, HGG’s are the leading cause of brain tumor death in both children and adults. And despite extraordinary progress in cancer research as a whole, survival rates for those diagnosed with an HGG have yet to improve.

shutterstock_30402241

But recent research from Stanford University scientists could one day help move the needle—and give renewed hope to the patients and their families affected by this devastating disease.

The study, published today in the journal Cell, found that one key driver for HGG’s deadly diagnosis is that the tumor can be stimulated to grow by the brain’s own neural activity—specifically the nerve activity in the brain’s cerebral cortex.

Michelle Monje, senior author of the study that was funded in part by two grants from CIRM, was initially surprised by these results, as they run counter to how most types of tumors grow. As she explained in today’s press release:

“We don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer. But we’ve shown that brain function is driving these brain cancers.”
 


By analyzing tumor cells extracted from HGG patients, and engrafting it onto mouse models in the lab, the researchers were able to pinpoint how the brain’s own activity was driving tumor growth.

The culprit: a protein called neuroligin-3 that appeared to be calling the shots. There are four distinct types of HGGs that affect the brain in vastly different ways—and have vastly different molecular and genetic characteristics. Interestingly, says Monje, neuroligin-3 played the same role in all of them.

What was so disturbing to the research team, says Monje, is that neuroligin-3 is an essential protein for overall brain development. Specifically, it helps maintain healthy growth and repair of brain tissue over time. In order to grow, HGG tumors hijack this critical protein.

The research team came to this conclusion after a series of experiments that delved deep into the molecular mechanisms that guide both brain activity and brain tumor development. They first employed a technique called optogenetics, whereby scientists use genetic manipulation to insert light-sensitive proteins into the brain cells, or neurons, of interest. This allowed scientists to activate these neurons—or deactivate them—at the ‘flick of a switch.’

When applying this technique to the tumor-engrafted mouse models, the team could then see that tumors grew significantly better when the neurons were switched on. The next step was to narrow it down to why. Additional biochemical analyses and testing on the mouse models confirmed that neuroligin-3 was being hijacked by the tumor to spur growth.

And when they dug deeper into the connection between neuroligin-3 and cancer, they found something even more disturbing. A detailed look at the Cancer Genome Atlas (a large public database of the genetics of human cancers), they found that HGG patients with higher levels of neuroligin-3 in their brain had shorter survival rates than those with lower levels of the same protein.

These results, while highlighting the particularly nefarious nature of this class of brain tumors, also presents enormous opportunity for researchers. Specifically, Monje hopes her team and others can find a way to block or nullify the presence of neuroligin-3 in the regions surrounding the tumor, creating a kind of barrier that can keep the size of the tumor in check. 


Molecular Trick Diminishes Appearance of Scars, Stanford Study Finds

Every scar tells a story, but that story may soon be coming to a close, as new research from Stanford University reveals clues to why scars form—and offers clues on how scarring could become a thing of the past.

Reported last week in the journal Science, the research team pinpointed the type of skin cell responsible for scarring and, importantly, also identified a molecule that, when activated, can actually prevent the skin cells from forming a scar. As one of the study’s senior authors Michael Longaker explained in a press release, the biomedical burden of scarring is vast.

Scars, both internal and external, present a significant biomedical burden.

Scars, both internal and external, present a significant biomedical burden.

“About 80 million incisions a year in this country heal with a scar, and that’s just on the skin alone,” said Longaker, who also co-directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack.”

Scars are normally formed when a type of skin cell called a fibroblast secretes a protein called collagen at the injury site. Collagen acts like a biological Band-Aid that supports and stabilizes the damaged skin.

In this study, which was funded in part by a grant from CIRM, Longaker, along with co-first authors Yuval Rinkevich and Graham Walmsley, as well as co-senior author and Institute Director Irving Weissman, focused their efforts on a type of fibroblast that appeared to play a role in the earliest stages of wound healing.

This type of fibroblast stands out because it secretes a particular protein called engrailed, which initial experiments revealed was responsible for laying down layers of collagen during healing. In laboratory experiments in mouse embryos, the researchers labeled these so-called ‘engrailed-positive fibroblast cells,’ or EPF cells, with a green fluorescent dye. This helped the team track how the cells behaved as the mouse embryo developed.

Interestingly, these cells were also engineered to self-destruct—activated with the application of diphtheria toxin—so the team could monitor what would happen in the absence of EPF cells entirely.

Their results revealed strong evidence that EPF cells were critical for scar formation. The scarring process was so tied to these EPF cells that when the team administered the toxin to shut them down, scarring reduced significantly.

Six days later the team found continued differences between mice with deactivated EPF cells, and a group of controls. Indeed, the experimental group had repaired skin that more closely resembled uninjured skin, rather than the distinctive scarring pattern that normally occurs.

Further examination of EPF cells’ precise function revealed a protein called CD26 and that blocking EPF’s production of CD26 had the same effect as shutting off EPF cells entirely. Wounds treated with a CD26 inhibitor had scars that covered only 5% of the original injury site, as opposed to 30%.

Pharmaceutical companies Merck and Novartis have already manufactured two types of CD26 inhibitor, originally developed to treat Type II diabetes, which could be modified to block CD26 production during wound healing—a prospect that the research team is examining more closely.

CIRM-Funded Scientists Build a Better Neuron; Gain New Insight into Motor Neuron Disease

Each individual muscle in our body—no matter how large or how small—is controlled by several types of motor neurons. Damage to one or more types of these neurons can give rise to some of the most devastating motor neuron diseases, many of which have no cure. But now, stem cell scientists at UCLA have manufactured a way to efficiently generate motor neuron subtypes from stem cells, thus providing an improved system with which to study these crucial cells.

“Motor neuron diseases are complex and have no cure; currently we can only provide limited treatments that help patients with some symptoms,” said senior author Bennett Novitch, in a news release. “The results from our study present an effective approach for generating specific motor neuron populations from embryonic stem cells to enhance our understanding of motor neuron development and disease.”

Normally, motor neurons work by transmitting signals between the brain and the body’s muscles. When that connection is severed, the individual loses the ability to control individual muscle movement. This is what happens in the case of amyotrophic lateral sclerosis, or ALS, also known as Lou Gehrig’s disease.

These images reveal the significance of the 'Foxp1 effect.' The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

These images reveal the significance of the ‘Foxp1 effect.’ The Foxp1 transcription factor is crucial to the normal growth and function of motor neurons involved in limb-movement.

Recent efforts had focused on ways to use stem cell biology to grow motor neurons in the lab. However, such efforts to generate a specific type of motor neuron, called limb-innervating motor neurons, have not been successful. This motor-neuron subtype is particularly affected in ALS, as it supplies nerves to the arms and legs—the regions usually most affected by this deadly disease.

In this study, published this week in Nature Communications, Novitch and his team, including first author Katrina Adams, worked to develop a better method to produce limb-innervating motor neurons. Previous efforts had only had a success rate of about 3 percent. But Novitch and Adams were able to boost that number five-fold, to 20 percent.

Specifically, the UCLA team—using both mouse and human embryonic stem cells—used a technique called ‘transcriptional programming,’ in order to coax these stem cells into become fully functional, limb-innervating motor neurons.

In this approach, which was funded in part by a grant from CIRM, the team added a single transcription factor (a type of protein that regulates gene function), which would then guide the stem cell towards becoming the right type of motor neuron. Here, Novitch, Adams and the team used the Foxp1 transcription factor to do the job.

Normally, Foxp1 is found in healthy, functioning limb-innervating motor neurons. But in stem cell-derived motor neurons, Foxp1 was missing. So the team reasoned that Foxp1 might actually be the key factor to successfully growing these neurons.

Their initial tests of this theory, in which they inserted Foxp1 into a developing chicken spinal cord (a widely used model for neurological research), were far more successful. This result, which is not usually seen with most unmodified stem-cell-derived motor neurons, illustrates the important role played by Foxp1.

The most immediate implications of this research is that now scientists can now use this method to conduct more robust studies that enhance the understanding of how these cells work and, importantly, what happens when things go awry.

Gene Therapy Beats Half-Matched Stem Cell Transplant in Side-by-Side Comparison to Treat ‘Bubble Baby’ Disease

If you are born with Severe Combined Immunodeficiency (SCID), your childhood is anything but normal. You don’t get to play with other kids, or be held by your parents. You can’t even breathe the same air. And, without treatment, you probably won’t live past your first year.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

This is the reality of SCID, also called “Bubble Baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. The only way to treat the disorder was with a fully matched stem cell transplant from a bone marrow donor, ideally from a sibling. But as you may have guessed, finding a match is extraordinarily rare. Until recently, the next best option was a ‘half-match’ transplant—usually from a parent. But now, scientists are exploring a third, potentially advantageous option: gene therapy. Late last year, we wrote about a promising clinical trial from UCLA researcher (and CIRM Grantee) Donald Kohn, whose team effectively ‘cured’ SCID in 18 children with the help of gene therapy. Experts still consider a fully matched stem cell transplant to be the gold standard of treatment for SCID. But are the second-tier contenders—gene therapy and half-matched transplant—both equally as effective? Until recently, no one had direct comparison. That all changes today, as scientists at the Necker Children’s Hospital in Paris compare in the journal Blood, for the first time, half-matched transplants and gene therapy—to see which approach comes out on top. The study’s lead author, Fabien Touzot, explained the importance of comparing these two methods:

“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”

So the team monitored a group of 14 SCID children who had been treated with gene therapy, and compared them to another group of 13 who had received the half-matched transplant. And the differences were staggering. Children in the gene therapy group showed an immune system vastly improved compared to the half-matched transplant group. In fact, in the six months following treatment, T-cell counts (an indicator of overall immune system health) rose to almost normal levels in more than 75% of the gene therapy patients. In the transplant group, that number was just over 25%. The gene therapy patients also showed better resilience against infections and had far fewer infection-related hospitalizations—all indictors that gene therapy may in fact be superior to a half-matched transplant. This is encouraging news say researchers. Finding a fully matched stem cell donor is incredibly rare. Gene therapy could then give countless families of SCID patients hope that their children could lead comparatively normal, healthy lives. “Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” explained Touzot. “These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach.” Hear more about how gene therapy could revolutionize treatment strategies for SCID in our recent interview with Donald Kohn:

Stem Cell Scientists Reconstruct Disease in a Dish; Gain Insight into Deadly Form of Bone Cancer

The life of someone with Li-Fraumeni Syndrome (LFS) is not a pleasant one. A rare genetic disorder that usually runs in families, this syndrome is characterized by heightened risk of developing cancer—multiple types of cancer—at a very young age.

People with LFS, as the syndrome is often called, are especially susceptible to osteosarcoma, a form of bone cancer that most often affects children. Despite numerous research advances, survival rates for this type of cancer have not improved in over 40 years.

shutterstock_142552177 But according to new research from Mount Sinai Hospital and School of Medicine, the prognosis for these patients may not be so dire in a few years.

Reporting today in the journal Cell, researchers describe how they used a revolutionary type of stem cell technology to recreate LFS in a dish and, in so doing, have uncovered the series of molecular triggers that cause people with LFS to have such high incidence of osteosarcoma.

The scientists, led by senior author Ihor Lemischka, utilized induced pluripotent stem cells, or iPSCs, to model LFS—and osteosarcoma—at the cellular level.

Discovered in 2006 by Japanese scientist Shinya Yamanaka, iPSC technology allows scientists to reprogram adult skin cells into embryonic-like stem cells, which can then be turned into virtually any cell in the body. In the case of a genetic disorder, such as LFS, scientists can transform skin cells from someone with the disorder into bone cells and grow them in the lab. These cells will then have the same genetic makeup as that of the original patient, thus creating a ‘disease in a dish.’ We have written often about these models being used for various diseases, particularly neurological ones, but not cancer.

“Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer,” said lead author and Mount Sinai postdoctoral fellow Dung-Fang Lee in today’s press release.

The team’s research centered on the protein p53. P53 normally acts as a tumor suppressor, keeping cell divisions in check so as not to divide out of control and morph into early-stage tumors. Previous research had revealed that 70% of people with LFS have a specific mutation in the gene that encodes p53. Using this knowledge and with the help of the iPSC technology, the team shed much-needed light on a molecular link between LFS and bone cancer. According to Lee:

“This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place.”

Specifically, the team discovered that the ultimate culprit of LFS bone cancer is an overactive p53 gene. Too much p53, it turns out, reduces the amount of another gene, called H19. This then leads to a decrease in the protein decorin. Decorin normally acts to help stem cells mature into healthy, bone-making cells, known as osteoblasts. Without it, the stem cells can’t mature. They instead divide over and over again, out of control, and ultimately cause the growth of dangerous tumors.

But those out of control cells can become a target for therapy, say researchers. In fact, the team found that artificially boosting H19 levels could have a positive effect.

“Our experiments showed that restoring H19 expression hindered by too much p53 restored “protective differentiation” of osteoblasts to counter events of tumor growth early on in bone cancer,” said Lemischka.

And, because mutations in p53 have been linked to other forms of bone cancer, the team is optimistic that these preliminary results will be able to guide treatment for bone cancer patients—whether they have LFS or not. Added Lemischka:

“The work has implications for the future treatment or prevention of LFS-associated osteosarcoma, and possibly for all forms of bone cancer driven by p53 mutations, with H19 and p53 established now as potential targets for future drugs.”

Learn more about how scientists are using stem cell technology to model disease in a dish in our special video series: Stem Cells In Your Face:

Cancer Cells Mimic Blood Vessels to Colonize the Body’s Farthest Reaches

Scientists at Cold Spring Harbor Laboratory have just uncovered the latest dirty trick in the cancer playbook—one that spurs the cancer cells to spread throughout the body and evade treatment. But importantly, they believe they may have found a way to counter it.

Reporting today in the journal Nature, Cold Spring Harbor researchers describe how tumor cells can form tubular networks that mimic blood vessels. It is this mimicry, the team argues, that plays a key role in helping the cancer spread throughout the body—and a significant hurdle to successfully treating the disease.

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Two adjacent sections of a mouse breast tumor. Tissue at left is stained so that normal blood vessels can be seen (black arrow). Extending from these vessels are blood filled channels (green arrows). On the right, the tissue is stained for a fluorescent protein expressed by the tumor cells. Here, blood-filled channels are actually formed by tumor cells in a process known as vascular mimicry. [Credit: Hannon Lab, CSHL]

Using mouse models of breast cancer, the team—led by Simon Knott—identified this phenomenon, called ‘vascular mimicry,’ and revealed that two genes, called Serpine2 and Slpi, were driving it. Made up of tumor cells literally stacked together, these tubular networks allowed oxygen and other nutrients to reach far-flung tumor cells throughout the body. This kept the tumor cells healthy, and helped them spread.

In today’s press release, Knott explained his initial reactions to this critical discovery:

“It’s very neat to watch and see cells evolve to have these capacities, but on the other hand it’s really scary to think that these cells are sitting there in people doing this.”

In laboratory experiments, the team found that boosting levels of Serpin2 and Slpi boosted the cancer’s ability to build these networks. Conversely, shutting down these two genes appeared to do the opposite. Knott argues that targeting the proteins that these two genes produce, as a way of shutting them off, may be a winning strategy:

“Targeting them might provide therapeutic benefits,” said Knott, “but we’re not sure yet.”

Indeed, research efforts over the past decade or more have tried to curb the production of these tubular networks of tumor cells, but with limited success. These drugs, called angiogenesis inhibitors, may not have worked as well as originally hoped because the underlying mechanism that creates this vascular mimicry—namely the genes Serpin2 and Slpi—was not targeted. Postdoctoral researcher Elvin Wagenblast, the paper’s first author, thinks they might have more success now:

“Maybe by targeting angiogenesis and also vascular mimicry at the same time we might actually have a better benefit in the clinic in the long run.”

This strategy is ultimately the goal of the team, but much work remains. Their most immediate next steps are to understand the process by which tumor cells pass through these tubular networks and infiltrate new areas of the body. But armed with this new-found knowledge of vascular mimicry, these and other researchers may be well on their way to outsmarting cancer, at least some of the time.

Building a Better Needle: CIRM-Funded Invention Gets Cells Into Brain More Safely, Efficiently

If NASA’s billion dollar Mars rovers deployed a bunch of dollar store party balloons to cushion the moment of impact, the mission would fail miserably. Likewise, the many years and millions of dollars spent on developing a stem cell-based therapy could be all for naught if the delivery of those precious cells into patients used cheap, inefficient tools.

That’s the subject of a recent TV interview with George Yu, who is CEO of Accurexa, a company that is developing and commercializing a novel syringe and needle device that could dramatically improve the delivery of cell therapies to the brain. The device was invented by UCSF neurosurgeon Daniel Lim with the support of a CIRM Tools and Technologies grant.

“So [Dr. Lim] participated in a phase 1 trial a few years ago where he was asked to deliver stem cell[-derived cells] to the brain and he didn’t really have adequate tools to do that, “ Yu explained in his interview with the New York-based finance and business TV program, New to the Street.

“The company that manufactured the stem cells spent millions of dollars in research but then they gave [Dr. Lim] a syringe and a needle that literally costs a couple of dollars. When he used that syringe and needle, which is a straight needle and injected those cells into the brain he actually saw a substantial amount of cells coming to the surface of the brain, which we call reflux, and that’s the reason he said there must be something better than this. And he applied for a grant, he got funded, and he invented the device. “

Not only does the standard straight syringe and needle cause a loss of transplanted cells due to reflux it also requires multiple injections in order to properly distribute the cell therapy in the brain. And with each injection, healthy brain tissue is damaged and increases the risk of stroke.

The Branched Point Device allows a well distributed cell transplantation into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

The Branched Point Device allows a well distributed transplantation of cells into the brain with just one injection site. (image credit: Stereotact Funct Neurosurg. 2013; 91(2): 92–103.)

Lim’s invention, called a Branched Point Device, avoids both cell reflux and the need for multiple injections. Instead of coming straight out of the needle tip, the cells are delivered through an opening that’s positioned on the side of the needle. So rather than re-injecting the needle, it’s incrementally rotated to deliver the cells in a different direction. With the use of a catheter that pokes through the needle, the cells can be distributed around the needle at different depths in a radial pattern much like the branches of a tree.

Use of the device in clinical trials may soon become a reality based on Yu’s comments in the interview:

“We’ve mostly completed our testing and the design of the device and we’re in the late stage of preparing a 510k submission to the FDA. So we expect that to happen this year. And once it’s FDA approved we can potentially sell the device.”

And because CIRM funded the development of this invention, the State of California is entitled to share in licensing revenue arising from the invention. Better still, the use of the device in clinical trials could provide more consistent, reliable results and a faster path to approval for stem cell-based therapies for neurodegenerative diseases like Parkinson’s.