Cell-based therapies have been the subject of much discussion regarding their potential role in enhancing central nervous system function for a number of pathologic conditions. Much of the current research has been in preclinical trials, with clinical trials in the phase I or I/II stage. Nevertheless, there is considerable interest in the public about the potential regenerative role that stem cells may have in improving function for these neurologic conditions. This review will describe the different types of stem cells that are available, review their possible effects, and discuss some of the variables that investigators need to consider when designing their studies. Current clinical research in the areas of stroke, traumatic brain injury, and neurodegenerative diseases (amyotrophic lateral sclerosis and Parkinson disease) will be reviewed. As this article is aimed at a rehabilitation audience, outcome measures, and the role of concurrent rehabilitation therapies will also be mentioned.
Posts Tagged Neurodegenerative
The three-pound organ that serves as command central for the human organism is certainly a marvel, just by virtue of the fact that the brain can appreciate its own awesomeness, even if it hasn’t quite perfected the flying car or even self-driving cars. Yet. Companies developing brain-computer interface technology are enabling humans to do things like send commands to computers by just flexing a bit of muscle. Still, there is much we don’t know about ourselves, no matter how much telepsychiatry we do. And that applies especially to medical conditions that affect the brain like epilepsy, a neurological condition for which there is no cure.
What is Epilepsy?
While most of us are probably familiar with some Hollywood-ized version of epilepsy in which someone starts flailing around after being hit by strobe lights on the disco floor, the reality is that epilepsy refers to a large group of neurological disorders that generally involve chronic, spontaneous seizures that vary greatly in how they manifest. The causes of epilepsy are also all over the place, from traumatic brain injuries and stroke to viral and bacterial infections to genetics.
It is considered a brain disorder, according to the U.S. Centers for Disease Control (CDC), though some researchers have suggested it could be classified as a neurodegenerative disease like Parkinson’s or Alzheimer’s. In fact, there is research that suggests a genetic link between epilepsy and neurodegenerative diseases.
Not surprisingly, many of the companies developing therapies for neurodegenerative diseases are also working on treatments for epilepsy and vice versa. For example, a new, well-funded joint venture involving Pfizer (PFE) and Bain Capital called Cerevel, which we profiled in our piece on Parkinson’s disease, is also in advanced clinical trials for an epileptic drug. Its GABA A positive modulator drug candidate targets GABA (Gamma-Aminobutyric Acid) neurotransmitters that block impulses between nerve cells in the brain, helping keep the nervous system chill.
Impacts of Epilepsy
More than 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally, according to the World Health Organization (WHO). The CDC estimates about 3.4 million Americans live with the condition. Globally, an estimated 2.4 million people are diagnosed with epilepsy each year. Interestingly, the disorder seems to target those who can least afford it: WHO said nearly 80% of people with epilepsy live in low- and middle-income countries.
A 2015 study of a bunch of other studies that estimated the cost of epilepsy in the United States found that epilepsy-specific costs probably average out to about $10,000 based on the variety of ranges, which means epilepsy costs the United States healthcare system about $34 billion, though the numbers are widely debated. Conversely, WHO says low-cost treatments are available, with daily medication coming as cheaply as $5 per year, so another win for the U.S. healthcare system.
Treatments for Epilepsy
There are more than 20 antiepileptic drugs used to treat epilepsy, usually to help prevent or slow the occurrence of seizures. Other therapies include surgery and electroceutical treatment in which electrical stimulation is applied, usually to the vagus nerve, the longest cranial nerve in the body. While many find relief from one or more of these options, a third of those who suffer from epilepsy are not able to manage their seizures, according to the U.S. National Institutes of Health (NIH). Below we take a look at a range of innovative therapies designed to detect, stop, or find a cure for epilepsy.
Brain Stimulation Therapies
In our article on electroceutical treatments, we highlighted a London company called LivaNova (LIVN) that offers an implantable Vagus Nerve Stimulation (VNS) therapy that has been approved by the U.S. Food and Drug Administration (FDA) to help treat those with partial seizures who do not respond to seizure medications. A medical device company with a lengthy track record of returning value to investors, Medtronic (MDT) got FDA pre-market approval last year for its Deep Brain Stimulation (DBS) therapy for use in reducing partial-onset seizure for those who have proven to not respond to three or more antiepileptic medications. DBS therapy delivers controlled electrical pulses to an area in the brain called the anterior nucleus of the thalamus, which is part of a network involved in seizures. Yet another company offering a variation of brain stimulation therapy is NeuroPace, which markets its responsive neurostimulation device, or RNS system, as “the first and only brain-responsive neurostimulation system designed to prevent epileptic seizures at their source.”
Artificial Intelligence to Detect, Predict, and Control Epilepsy
The NIH is funding further research into implantable devices that can detect, predict, and stop a seizure before it happens, “working closely with industry partners to develop pattern-recognition algorithms,” which sounds an awful lot like artificial intelligence and machine learning will be at the forefront of some future diagnostics and treatment. AI in healthcare has been an ongoing theme around here, with a recent dive into AI and mental health. Back to AI and epilepsy: A group of neurologists at the Medical University of South Carolina developed a new method based on artificial intelligence to predict which patients will see success with surgical procedures designed to stop seizures. Sounds like a great idea to learn beforehand if it’s necessary to crack open your skull.
A Boston area startup called Empatica, spun out from MIT in 2011, has raised $7.8 million for a smartwatch that detects possible seizures by monitoring subtle electrical changes across the surface of the skin. Other methods normally rely on electrical activity in the brain that tracks and records brain wave patterns called an electroencephalogram. Empatica’s seizure detection algorithm, on the other hand, can detect complex physiological patterns from electrodermal activity that is most likely to accompany a convulsive seizure. Psychology Today reportedthat the device, Embrace Watch, received FDA approval earlier this year for seizure control in children after getting the green light for the technology for adults in 2018.
AI and drug discovery for better epileptic drug candidates is yet another application that we would expect to see grow in the coming years. Silicon Valley-based startup System1 Biosciences raised $25 million last year, which included Pfizer among its dozen investors. System1 builds a sort of brain model for testing drug candidates using stem cell lines derived from patients with brain disease. The company uses robotic automation to develop these three-dimensional cerebral organoids, allowing it to generate huge datasets in a relatively short amount of time, then applying “advanced data analysis” (also AI?) to detect patterns that might match the characteristics of a neurological disease (what it refers to as deep phenotypes) such as epilepsy with novel treatments.
Cannabis for Controlling Seizures
We’ve written extensively about the suddenly booming hemp CBD market, noting that the FDA approved a CBD-based drug for epilepsy last year in our recent article on the best certified CBD oils on the market. However, we’ve only briefly profiled the company behind Epidiolex for treating rare forms of epilepsy, GW Pharmaceuticals (GWPH). Sporting a market cap just south of $5 billion, GW Pharmaceuticals has taken in about $300 million in post-IPO equity since our article, bringing total post-IPO equity funding to about $568 million. Aside from its successful epileptic drug, GW also developed the world’s first cannabis-based prescription medicine for the treatment of spasticity due to multiple sclerosis that is available in 25 countries outside the United States.
Back on the epilepsy side, Epidiolex has been approved for two rare forms of epilepsy, with clinical trials underway for two more rare neurological disorders associated with seizures – tuberous sclerosis complex and Rett syndrome. Also in the pipeline is a drug dubbed CBDV (GWP42006) that’s also for treating epileptic seizures, though the results of a trial last year were not encouraging. The same compound is also being investigated for autism. Be sure to check out our article on Charlotte’s Web, a CBD company that came about because of epilepsy.
Helping Cells Get Their Vitamin K
Neuroene Therapeutics is a small startup spun out of the Medical University of South Carolina that recently picked up $1.5 million in funding to tests its lead drug compounds, which are analogous to the naturally occurring form of vitamin K that is essential for brain health. In particular, the lab-developed vitamin K protects the integrity of the cell’s mitochondria, which serves as a sort of power plant for brain cells, helping the neural circuit fire better. Unfortunately, you can’t get the effect from simply eating a bowl of Special K each morning covered in an organic sugar substitute, so the company is developing a method to deliver the effects directly to the brain.
A Nasal Spray to Stop Seizures
Founded in 2007 near San Diego, Neurelis licenses, develops, and commercializes treatments for epilepsy and other neurological diseases. It has raised $44.8 million in disclosed funding, most coming in a $40.5 million venture round last November. The company’s flagship product is called Valtoco, a formulation that incorporates diazepam, an existing drug used to control seizures and alcohol withdrawal, with a vitamin E-based solution that is delivered using a nasal spray when a sudden seizure episode occurs. The product uses an absorption enhancement technology called Intravail developed by another San Diego area company called Aegis Therapeutics that Neurelis acquired in December last year. Neurelis submitted Valtoco to the FDA for approval in September.
While many people with epileptic conditions can control their seizures with many of the current medications or other therapies available now, there’s a big chunk of the population that is living with uncertainty. Considering the strong link between neurological disorders like epilepsy and certain neurodegenerative disorders, expect to see some good synergies in the next five to 10 years, especially as automation and advanced analytics using AI start connecting the dots between genetics, biochemistry, and brain disorders.
What’s the most transformative thing that you can do for your brain today? Exercise! says neuroscientist Wendy Suzuki. Get inspired to go to the gym as Suzuki discusses the science of how working out boosts your mood and memory — and protects your brain against neurodegenerative diseases like Alzheimer’s.
This talk was presented at an official TED conference, and was featured by our editors on the home page.
What if I told you there was something that you can do right now that would have an immediate, positive benefit for your brain including your mood and your focus? And what if I told you that same thing could actually last a long time and protect your brain from different conditions like depression, Alzheimer’s disease or dementia. Would you do it? Yes!
I am talking about the powerful effects of physical activity. Simply moving your body,has immediate, long-lasting and protective benefits for your brain. And that can last for the rest of your life. So what I want to do today is tell you a story about how I used my deep understanding of neuroscience, as a professor of neuroscience, to essentially do an experiment on myself in which I discovered the science underlying why exercise is the most transformative thing that you can do for your brain today. Now, as a neuroscientist, I know that our brains, that is the thing in our head right now, that is the most complex structure known to humankind. But it’s one thing to talk about the brain,and it’s another to see it.
So here is a real preserved human brain. And it’s going to illustrate two key areas that we are going to talk about today. The first is the prefrontal cortex, right behind your forehead, critical for things like decision-making, focus, attention and your personality.The second key area is located in the temporal lobe, shown right here. You have two temporal lobes in your brain, the right and the left, and deep in the temporal lobe is a key structure critical for your ability to form and retain new long-term memories for facts and events. And that structure is called the hippocampus. So I’ve always been fascinated with the hippocampus. How could it be that an event that lasts just a moment, say, your first kiss, or the moment your first child was born, can form a memory that has changed your brain, that lasts an entire lifetime? That’s what I want to understand. I wanted to start and record the activity of individual brain cells in the hippocampus as subjects were forming new memories. And essentially try and decode how those brief bursts of electrical activity, which is how neurons communicate with each other, how those brief bursts either allowed us to form a new memory, or did not.
But a few years ago, I did something very unusual in science. As a full professor of neural science, I decided to completely switch my research program. Because I encountered something that was so amazing, with the potential to change so many lives that I had to study it. I discovered and I experienced the brain-changing effects of exercise. And I did it in a completely inadvertent way. I was actually at the height of all the memory work that I was doing — data was pouring in, I was becoming known in my field for all of this memory work. And it should have been going great. It was, scientifically. But when I stuck my head out of my lab door, I noticed something. I had no social life. I spent too much time listening to those brain cells in a dark room, by myself. (Laughter) I didn’t move my body at all. I had gained 25 pounds. And actually, it took me many years to realize it, I was actually miserable. And I shouldn’t be miserable. And I went on a river-rafting trip — by myself, because I had no social life.And I came back —
thinking, “Oh, my God, I was the weakest person on that trip.” And I came back with a mission. I said, “I’m never going to feel like the weakest person on a river-rafting trip again.” And that’s what made me go to the gym. And I focused my type-A personalityon going to all the exercise classes at the gym. I tried everything. I went to kickbox, dance, yoga, step class, and at first it was really hard. But what I noticed is that after every sweat-inducing workout that I tried, I had this great mood boost and this great energy boost. And that’s what kept me going back to the gym. Well, I started feeling stronger. I started feeling better, I even lost that 25 pounds.
And now, fast-forward a year and a half into this regular exercise program and I noticed something that really made me sit up and take notice. I was sitting at my desk, writing a research grant, and a thought went through my mind that had never gone through my mind before. And that thought was, “Gee, grant-writing is going well today.” And all the scientists —
yeah, all the scientists always laugh when I say that, because grant-writing never goes well. It is so hard; you’re always pulling your hair out, trying to come up with that million-dollar-winning idea. But I realized that the grant-writing was going well,because I was able to focus and maintain my attention for longer than I had before.And my long-term memory — what I was studying in my own lab — seemed to be better in me. And that’s when I put it together.
Maybe all that exercise that I had included and added to my life was changing my brain. Maybe I did an experiment on myself without even knowing it. So as a curious neuroscientist, I went to the literature to see what I could find about what we knewabout the effects of exercise on the brain. And what I found was an exciting and a growing literature that was essentially showing everything that I noticed in myself.Better mood, better energy, better memory, better attention. And the more I learned,the more I realized how powerful exercise was. Which eventually led me to the big decision to completely shift my research focus. And so now, after several years of really focusing on this question, I’ve come to the following conclusion: that exercise is the most transformative thing that you can do for your brain today for the following three reasons.
Number one: it has immediate effects on your brain. A single workout that you do will immediately increase levels of neurotransmitters like dopamine, serotonin and noradrenaline. That is going to increase your mood right after that workout, exactly what I was feeling. My lab showed that a single workout can improve your ability to shift and focus attention, and that focus improvement will last for at least two hours.And finally, studies have shown that a single workout will improve your reaction timeswhich basically means that you are going to be faster at catching that cup of Starbucks that falls off the counter, which is very, very important.
But these immediate effects are transient, they help you right after. What you have to do is do what I did, that is change your exercise regime, increase your cardiorespiratory function, to get the long-lasting effects. And these effects are long-lasting because exercise actually changes the brain’s anatomy, physiology and function. Let’s start with my favorite brain area, the hippocampus. The hippocampus —or exercise actually produces brand new brain cells, new brain cells in the hippocampus, that actually increase its volume, as well as improve your long-term memory, OK? And that including in you and me.
Number two: the most common finding in neuroscience studies, looking at effects of long-term exercise, is improved attention function dependent on your prefrontal cortex. You not only get better focus and attention, but the volume of the hippocampus increases as well. And finally, you not only get immediate effects of mood with exercise but those last for a long time. So you get long-lasting increases in those good mood neurotransmitters.
But really, the most transformative thing that exercise will do is its protective effects on your brain. Here you can think about the brain like a muscle. The more you’re working out, the bigger and stronger your hippocampus and prefrontal cortex gets. Why is that important? Because the prefrontal cortex and the hippocampus are the two areas that are most susceptible to neurodegenerative diseases and normal cognitive decline in aging. So with increased exercise over your lifetime, you’re not going to cure dementia or Alzheimer’s disease, but what you’re going to do is you’re going to create the strongest, biggest hippocampus and prefrontal cortex so it takes longer for these diseases to actually have an effect. You can think of exercise, therefore, as a supercharged 401K for your brain, OK? And it’s even better, because it’s free.
And so I’m going to tell you the answer to that question. First, good news: you don’t have to become a triathlete to get these effects. The rule of thumb is you want to get three to four times a week exercise minimum 30 minutes an exercise session, and you want to get aerobic exercise in. That is, get your heart rate up. And the good news is, you don’t have to go to the gym to get a very expensive gym membership.Add an extra walk around the block in your power walk. You see stairs — take stairs.And power-vacuuming can be as good as the aerobics class that you were going to take at the gym.
So I’ve gone from memory pioneer to exercise explorer. From going into the innermost workings of the brain, to trying to understand how exercise can improve our brain function, and my goal in my lab right now is to go beyond that rule of thumb that I just gave you — three to four times a week, 30 minutes. I want to understand the optimum exercise prescription for you, at your age, at your fitness level, for your genetic background, to maximize the effects of exercise today and also to improve your brain and protect your brain the best for the rest of your life.
[ARTICLE] A Review of Stem Cell Therapy for Acquired Brain Injuries and Neurodegenerative Central Nervous System Diseases – Full Text
Potential Roles That Stem Cells May Play in Regeneration
Stem cells may exert positive effects on the recovery process in a number of ways. Some cells have the ability to replicate and play a direct role in the repair of damaged neural tissue. These neural progenitor or neural stem cells (NSCs) may differentiate into different cell types and may be subsumed to roles of previously damaged or lost neurons. Such cells have been studied in a number of clinical conditions, but ethical issues have arisen, primarily because embryonic or fetal tissues have often been used. As these are allogeneic transplants, efforts must be taken to suppress the immune response, which may lead to complications. Additionally, concerns regarding tumorigenicity are greater for these cells because of their replicative ability . Adult neural stem cells can be found in some areas of the human brain including the subventricular zone and the hippocampal dentate gyrus . These are pluripotent cells that can replicate and differentiate based on intrinsic and environmental factors. They also have the ability to migrate, and differentiation may be driven by their ultimate location . There is the possibility that these cells can be cultured and engineered to carry out specific functions based on modulation of these factors, but much needs to be learned in order to achieve this goal .
Induced pluripotent stem cells (IPSCs) can also be generated from adult cells. They are reprogrammed by transcription factors into a more embryonic state. It is possible to perform this in an autologous fashion (the patient is the source for his or her IPSCs), although this can be difficult as this is an inefficient process that may take time to produce adequate cell numbers. Some concerns regarding tumorigenicity also exist for this strategy. Mesenchymal stem cells (MSCs) are another option for cell-based therapies. Autologous and allogeneic sources for these cells are available. These cells usually do not differentiate into neural cells. Rather, it is believed that their primary role in neural recovery is by producing trophic factors into their environment to stimulate endogenous neurogenesis and repair as well as modulating inflammation . MSCs do not appear to have the potential to become tumorigenic. However, they may have an immunosuppressive effect that, among other complications, might increase the risk of tumor formation .
The United States Food and Drug Administration (FDA) has on several occasions produced policies that have provided guidance regarding the use of these products to both protect consumers and support the ongoing research and development of regenerative medicine products in general. The stem cells discussed here are regenerative medicine therapies, and there are procedures that must be followed in clinical trials. The FDA has recently made efforts to try to “fast-track” some regenerative medicine therapies, especially those that address “serious diseases and conditions” .[…]