Neuroscience

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Posts tagged drug development

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Alzheimer’s disease drug-development pipeline: few candidates, frequent failures Introduction Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. Methods We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline. Results During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure). Conclusions The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support. Full Article (Image: Shutterstock)

Alzheimer’s disease drug-development pipeline: few candidates, frequent failures

Introduction

Alzheimer’s disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.

Methods

We examined Clinicaltrials.gov, a public website that records ongoing clinical trials. We examined the decade of 2002 to 2012, to better understand AD-drug development. We reviewed trials by sponsor, sites, drug mechanism of action, duration, number of patients required, and rate of success in terms of advancement from one phase to the next. We also reviewed the current AD therapy pipeline.

Results

During the 2002 to 2012 observation period, 413 AD trials were performed: 124 Phase 1 trials, 206 Phase 2 trials, and 83 Phase 3 trials. Seventy-eight percent were sponsored by pharmaceutical companies. The United States of America (U.S.) remains the single world region with the greatest number of trials; cumulatively, more non-U.S. than U.S. trials are performed. The largest number of registered trials addressed symptomatic agents aimed at improving cognition (36.6%), followed by trials of disease-modifying small molecules (35.1%) and trials of disease-modifying immunotherapies (18%). The mean length of trials increases from Phase 2 to Phase 3, and the number of participants in trials increases between Phase 2 and Phase 3. Trials of disease-modifying agents are larger and longer than those for symptomatic agents. A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).

Conclusions

The Clinicaltrials.gov database demonstrates that relatively few clinical trials are undertaken for AD therapeutics, considering the magnitude of the problem. The success rate for advancing from one phase to another is low, and the number of compounds progressing to regulatory review is among the lowest found in any therapeutic area. The AD drug-development ecosystem requires support.

Full Article

(Image: Shutterstock)

Filed under alzheimer's disease drug development health science

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How a new approach to funding Alzheimer’s research could pay off More than 5 million Americans suffer from Alzheimer’s disease, the affliction that erodes memory and other mental capacities, but no drugs targeting the disease have been approved by the U.S. Food and Drug Administration since 2003. Now a paper by an MIT professor suggests that a revamped way of financing Alzheimer’s research could spur the development of useful new drugs for the illness. “We are spending tremendous amounts of resources dealing with this disease, but we don’t have any effective therapies for it,” says Andrew Lo, the Charles E. and Susan T. Harris Professor of Finance and director of the Laboratory for Financial Engineering at the MIT Sloan School of Management. “It really imposes a tremendous burden on society, not just for the afflicted, but also for those who care for them.” Lo and three co-authors propose creating a public-private partnership that would fund research for a diverse array of drug-discovery projects simultaneously. Such an approach would increase the chances of a therapeutic breakthrough, they say, and the inclusion of public funding would help mitigate the risks and costs of Alzheimer’s research for the private sector. There would be a long-term public-sector payoff, according to the researchers: Government funding for Alzheimer’s research would pale in comparison to the cost of caring for Alzheimer’s sufferers in public health-care programs. The paper’s model of the new funding approach calls for an outlay of $38.4 billion over 13 years for research; the costs of Medicare and Medicaid support for Alzheimer’s patients in 2014 alone is estimated to be $150 billion. “Having parallel development would obviously decrease the waiting time, but it increases the short-run need for funding,” Lo says. “Given how much of an urgent need there is for Alzheimer’s therapies, it has to be the case that if you develop a cure, you’re going to be able to recoup your costs and then some.” In fact, the paper’s model estimates a double-digit return on public investment over the long run. Lo adds: “Can we afford it? I think a more pressing question is, ‘Can we afford not to do something about this now?’” Modeling the odds of success The paper, “Parallel Discovery of Alzheimer’s Therapeutics,” was published today in Science Translational Medicine. Along with Lo, the co-authors of the piece are Carole Ho of the biotechnology firm Genentech, Jayna Cummings of MIT Sloan, and Kenneth Kosik of the University of California at Santa Barbara. The main hypothesis on the cause of Alzheimer’s involves amyloid deposition, the buildup of plaques in the brain that impair neurological function; most biomedical efforts to tackle the disease have focused on this issue. For the study, Ho and Kosik, leading experts in Alzheimer’s research, compiled a list of 64 conceivable approaches to drug discovery, addressing a range of biological mechanisms that may be involved in the disease. A fund backing that group of research projects might expand the chances of developing a drug that could, at a minimum, slow the progression of the disease. On the other hand, it might not increase the odds of success so much that pharmaceutical firms and biomedical investment funds would plow money into the problem. “Sixty-four projects are a lot more than what’s being investigated today, but it’s still way shy of the 150 or 200 that are needed to mitigate the financial risks of an Alzheimer’s-focused fund,” Lo says. The model assumes 13 years for the development of an individual drug, including clinical trials, and estimates the success rates for drug development. Given 150 trials, the odds of at least two successful trials are 99.59 percent. Two successful trials, Lo says, is what it would take to make the investment — a series of bonds issued by the fund — profitable and attractive to a broad range of investors. “With a sufficiently high likelihood of success, you can issue debt to attract a large group of bondholders who would be willing to put their money to work,” Lo says. “The enormous size of bond markets translates into enormous potential funding opportunities for developing these therapeutics.” Stakeholders everywhere To be clear, Lo says, Alzheimer’s drug development is a very difficult task, since researchers often have to identify a pool of potential patients well before symptoms occur, in order to see how well therapies might work on delaying the onset of the disease. Compared with the development of new drugs to treat other diseases, “Alzheimer’s drug development is more expensive, takes longer, and needs a larger sample of potential patients,” Lo acknowledges. However, since the number of Americans suffering from Alzheimer’s is projected to double by 2050, according to the Alzheimer’s Association, an advocacy group, Lo stresses the urgency of the task at hand.”

How a new approach to funding Alzheimer’s research could pay off

More than 5 million Americans suffer from Alzheimer’s disease, the affliction that erodes memory and other mental capacities, but no drugs targeting the disease have been approved by the U.S. Food and Drug Administration since 2003. Now a paper by an MIT professor suggests that a revamped way of financing Alzheimer’s research could spur the development of useful new drugs for the illness.

“We are spending tremendous amounts of resources dealing with this disease, but we don’t have any effective therapies for it,” says Andrew Lo, the Charles E. and Susan T. Harris Professor of Finance and director of the Laboratory for Financial Engineering at the MIT Sloan School of Management. “It really imposes a tremendous burden on society, not just for the afflicted, but also for those who care for them.”

Lo and three co-authors propose creating a public-private partnership that would fund research for a diverse array of drug-discovery projects simultaneously. Such an approach would increase the chances of a therapeutic breakthrough, they say, and the inclusion of public funding would help mitigate the risks and costs of Alzheimer’s research for the private sector.

There would be a long-term public-sector payoff, according to the researchers: Government funding for Alzheimer’s research would pale in comparison to the cost of caring for Alzheimer’s sufferers in public health-care programs. The paper’s model of the new funding approach calls for an outlay of $38.4 billion over 13 years for research; the costs of Medicare and Medicaid support for Alzheimer’s patients in 2014 alone is estimated to be $150 billion.

“Having parallel development would obviously decrease the waiting time, but it increases the short-run need for funding,” Lo says. “Given how much of an urgent need there is for Alzheimer’s therapies, it has to be the case that if you develop a cure, you’re going to be able to recoup your costs and then some.” In fact, the paper’s model estimates a double-digit return on public investment over the long run.

Lo adds: “Can we afford it? I think a more pressing question is, ‘Can we afford not to do something about this now?’”

Modeling the odds of success

The paper, “Parallel Discovery of Alzheimer’s Therapeutics,” was published today in Science Translational Medicine. Along with Lo, the co-authors of the piece are Carole Ho of the biotechnology firm Genentech, Jayna Cummings of MIT Sloan, and Kenneth Kosik of the University of California at Santa Barbara.

The main hypothesis on the cause of Alzheimer’s involves amyloid deposition, the buildup of plaques in the brain that impair neurological function; most biomedical efforts to tackle the disease have focused on this issue. For the study, Ho and Kosik, leading experts in Alzheimer’s research, compiled a list of 64 conceivable approaches to drug discovery, addressing a range of biological mechanisms that may be involved in the disease.

A fund backing that group of research projects might expand the chances of developing a drug that could, at a minimum, slow the progression of the disease. On the other hand, it might not increase the odds of success so much that pharmaceutical firms and biomedical investment funds would plow money into the problem.

“Sixty-four projects are a lot more than what’s being investigated today, but it’s still way shy of the 150 or 200 that are needed to mitigate the financial risks of an Alzheimer’s-focused fund,” Lo says.

The model assumes 13 years for the development of an individual drug, including clinical trials, and estimates the success rates for drug development. Given 150 trials, the odds of at least two successful trials are 99.59 percent. Two successful trials, Lo says, is what it would take to make the investment — a series of bonds issued by the fund — profitable and attractive to a broad range of investors.

“With a sufficiently high likelihood of success, you can issue debt to attract a large group of bondholders who would be willing to put their money to work,” Lo says. “The enormous size of bond markets translates into enormous potential funding opportunities for developing these therapeutics.”

Stakeholders everywhere

To be clear, Lo says, Alzheimer’s drug development is a very difficult task, since researchers often have to identify a pool of potential patients well before symptoms occur, in order to see how well therapies might work on delaying the onset of the disease.

Compared with the development of new drugs to treat other diseases, “Alzheimer’s drug development is more expensive, takes longer, and needs a larger sample of potential patients,” Lo acknowledges.

However, since the number of Americans suffering from Alzheimer’s is projected to double by 2050, according to the Alzheimer’s Association, an advocacy group, Lo stresses the urgency of the task at hand.”

Filed under alzheimer's disease drug development health medicine neuroscience science

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Newly Identified Brain Cancer Mutation Will Aid Drug Development

A collaborative effort between Duke Medicine researchers and neurosurgeons and scientists in China has produced new genetic insights into a rare and deadly form of childhood and young adult brain cancer called brainstem glioma.

The researchers identified a genetic mutation in the tumor cells that plays a role in both the growth and the death of a cell. Additionally, the mutation to the newly identified gene may also contribute to the tumor’s resistance to radiation.

The findings, published online in the journal Nature Genetics on June 1, 2014, provide both immediate and long-term benefits. Knowing that this mutation may render radiation ineffective, patients could be spared that therapy. The mutation would also serve as a strong candidate for drug development.

The researchers conducted genetic tests and found that many of the tumor cells had a mutation in a gene called PPM1D, which causes cells to proliferate and avoid natural death. It is the first time this mutation has been found to be a major driving force in the development of brainstem gliomas; it is not evident in other brain tumors.

If tumors have this PPM1D mutation, they do not have another more common genetic mutation to the TP53 gene, a tumor suppressor that, when defective, is linked to half of all cancers.

“This finding has immediate clinical applications, because either mutation - PPM1D or TP53 – cause the tumor cells to be resistant to radiation,” said senior author Hai Yan, M.D., Ph.D., a professor of pathology at Duke University School of Medicine. “Knowing that could spare patients from an ineffective treatment approach.”

Additionally, the PPM1D genetic mutation is a strong candidate for new drug development.

“This finding gives us a clue as to why these particular tumors are growing inappropriately,” said co-author Zachary Reitman, M.D., Ph.D., a research associate at Duke. “These clues may help us to design better treatments for this type of cancer.”

Yan said his lab is working to identify new treatments that could target the PPM1D genetic mutation and shut down its cancer-growing capabilities.

“PPM1D is itself a target for drug development, because the gene mutation causes cells to avoid death and proliferate,” Yan said. “In drug development, it’s easier to turn that growth function off than it is to switch on the cell’s defective tumor suppression mechanism.”

(Source: corporate.dukemedicine.org)

Filed under brainstem glioma genetic mutation PPM1D drug development neuroscience science

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Unprecedented detail of intact neuronal receptor offers blueprint for drug developers Biologists at Cold Spring Harbor Laboratory (CSHL) report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke. The team’s atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds. The NMDA receptor is a massive multi-subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor’s function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases. Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published today in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated. “Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough,” says Furukawa. “To understand how this complex functions you need to see it all together, fully assembled.” For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. “The ‘basket’ is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron,” explains Furukawa. An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel “gate” is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane. When the ion channel “gate” opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can’t jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain. The “balloon” portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. “We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane,” says Furukawa. “Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors.” This information will be critical as scientists work to develop drugs that control the NMDA receptor. “Our structure defines the interfaces where multiple subunits and domains contact one another,” says Furukawa. “In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”

Unprecedented detail of intact neuronal receptor offers blueprint for drug developers

Biologists at Cold Spring Harbor Laboratory (CSHL) report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.

The team’s atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds.

The NMDA receptor is a massive multi-subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor’s function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases.

Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published today in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated.

“Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough,” says Furukawa. “To understand how this complex functions you need to see it all together, fully assembled.”

For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. “The ‘basket’ is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron,” explains Furukawa.

An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel “gate” is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane.

When the ion channel “gate” opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can’t jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain.

The “balloon” portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. “We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane,” says Furukawa. “Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors.”

This information will be critical as scientists work to develop drugs that control the NMDA receptor. “Our structure defines the interfaces where multiple subunits and domains contact one another,” says Furukawa. “In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”

Filed under NMDA receptor drug development ion channel neuroscience science

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A new role for sodium in the brain

Researchers at McGill University have found that sodium – the main chemical component in table salt – is a unique “on/off” switch for a major neurotransmitter receptor in the brain. This receptor, known as the kainate receptor, is fundamental for normal brain function and is implicated in numerous diseases, such as epilepsy and neuropathic pain.

image

Prof. Derek Bowie and his laboratory in McGill’s Department of Pharmacology and Therapeutics, worked with University of Oxford researchers to make the discovery. By offering a different view of how the brain transmits information, their research highlights a new target for drug development. The findings are published in the journal Nature Structural & Molecular Biology.

Balancing kainate receptor activity is the key to maintaining normal brain function. For example, in epilepsy, kainate activity is thought to be excessive. Thus, drugs which would shut down this activity are expected to be beneficial.

“It has been assumed for decades that the “on/off” switch for all brain receptors lies where the neurotransmitter binds,” says Prof. Bowie, who also holds a Canada Research Chair in Receptor Pharmacology. “However, we found a completely separate site that binds individual atoms of sodium and controls when kainate receptors get turned on and off.”

The sodium switch is unique to kainate receptors, which means that drugs designed to stimulate this switch, should not act elsewhere in the brain. This would be a major step forward, since drugs often affect many locations, in addition to those they were intended to act on, producing negative side-effects as a result. These so called “off-target effects” for drugs represent one of the greatest challenges facing modern medicine.

“Now that we know how to stimulate kainate receptors, we should be able to design drugs to essentially switch them off,” says Dr. Bowie.

Dr. Philip Biggin’s lab at Oxford University used computer simulations to predict how the presence or absence of sodium would affect the kainate receptor.

(Source: mcgill.ca)

Filed under sodium kainate receptor brain function drug development neuroscience science

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NIH launches neurological drug development projects

New projects will target Fragile X syndrome, nicotine addiction, and age-related macular degeneration

The National Institutes of Health has launched three innovative projects that will focus on development of therapeutics for Fragile X syndrome, nicotine addiction, and age-related macular degeneration (AMD). These projects are funded through the NIH Blueprint Neurotherapeutics Network which provides access to a variety of drug development resources.

image

“We are excited about the opportunity to apply cutting-edge science to the pursuit of novel treatments for these debilitating disorders” said Rebecca Farkas, Ph.D., program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), Office of Translational Research.

The purpose of the NIH Blueprint is to provide in-depth research capabilities to increase the success rate of innovative drug discovery efforts. The program uses a virtual pharma model to provide researchers with access to support and resources that have been traditionally available to large pharmaceutical companies.

Partnerships between NIH program staff and awarded research teams are designed to bridge the funding gap between ground-breaking laboratory research and industry adoption. NIH staff helps investigators work with veteran industry drug development consultants and contract research organization capabilities from the discovery stage through preliminary clinical trials. In addition, each investigator maintains sole ownership of intellectual property associated with his or her project

NIH launched the Blueprint Neurotherapeutics Network in 2011. Including these three awards, 14 drug discovery programs have been funded as part of the program and 10 are currently active (see: http://neuroscienceblueprint.nih.gov/bpdrugs/bpn.htm).

The newly-funded investigators and their organizations are:

  • Sage Therapeutics, Cambridge, Mass.
    Principal Investigator: Al Robichaud, Ph.D.
    Disorder: Fragile X syndrome
    Project Summary: Fragile X syndrome is a genetic disorder linked to a range of neurodevelopmental disorders including learning disabilities and cognitive impairment. Many patients experience general and social anxiety yet benzodiazepines, which are drugs typically used to treat anxiety disorders, provide little relief. Their anxiety has been linked to reduced activity in the brain by a protein called, the GABA A receptor. Sage Therapeutics is developing positive allosteric modulators, designed to enhance the receptor’s activity and possibly relieve the anxiety.
  • The Scripps Research Institute, Jupiter, Fla.
    Principal Investigator: Paul J. Kenny, Ph.D.
    Disorder: nicotine addiction
    Project Summary: Nicotine addiction has been attributed to the stimulatory effects of nicotine binding to brain proteins called orexin 1 receptors. Dr. Kenny and colleagues will develop selective receptor antagonists as potential smoking cessation aids to treat people who have attempted to quit smoking but faced high relapse rates and significant side effects.
  •  University of Utah, Salt Lake City
    Principal Investigator: Dean Yaw Li, Ph.D.
    Disorder: age-related macular degeneration
    Project Summary: Age-related macular degeneration is a leading cause of blindness in the United States. One form, called wet AMD, is associated with inflammation and blood vessel leakage in the retina, the eye’s light-sensitive tissue. Dean Li and his colleagues are developing small molecules that inhibit the activity of Arf6, a molecule known to help control inflammation and blood vessel leakage. This novel approach may lead to effective therapies for treating patients who do not respond to current wet AMD therapies.

(Source: nih.gov)

Filed under fragile x syndrome nicotine addiction macular degeneration drug development neurology neuroscience science

195 notes

Scientists advance understanding of brain receptor; may help fight neurological disorders For several years, the pharmaceutical industry has tried to develop drugs that target a specific neurotransmitter receptor in the brain, the NMDA receptor. This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression. But drug companies have had little success developing clinically effective drugs that target this receptor. Now, researchers at Oregon Health & Science University’s Vollum Institute believe they may understand why. And what they’ve discovered may help in the development of new therapies for these conditions. In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties. As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action. What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts. "What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn’t there in high quantities. The target they’ve been looking for isn’t the target that’s there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar’s co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory. Tovar said these findings could provide a new target for drug development. "If you know what’s there, then you know what to go after — you just have to figure out how to do it," Tovar said. The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial. "NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said. "From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective." (Image: iStockphoto)

Scientists advance understanding of brain receptor; may help fight neurological disorders

For several years, the pharmaceutical industry has tried to develop drugs that target a specific neurotransmitter receptor in the brain, the NMDA receptor. This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression.

But drug companies have had little success developing clinically effective drugs that target this receptor.

Now, researchers at Oregon Health & Science University’s Vollum Institute believe they may understand why. And what they’ve discovered may help in the development of new therapies for these conditions.

In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties.

As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action.

What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts.

"What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn’t there in high quantities. The target they’ve been looking for isn’t the target that’s there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar’s co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory.

Tovar said these findings could provide a new target for drug development.

"If you know what’s there, then you know what to go after — you just have to figure out how to do it," Tovar said.

The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial.

"NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said.

"From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective."

(Image: iStockphoto)

Filed under neurological disorders NMDA receptors learning synapses drug development neuroscience science

46 notes

New research findings on the brain’s guardian cells

Researcher Johan Jakobsson and his colleagues have now published their results in Nature Communications.

At present, researchers know very little about exactly how microglia work. At the same time, there is a lot of curiosity and high hopes among brain researchers that greater understanding of microglia could lead to entirely new drug development strategies for various brain diseases”, says Johan Jakobsson, research group leader at the Division of Molecular Neurogenetics at Lund University.

What the researchers have now succeeded in identifying is a deviation in the structure of the microglia cells, which makes it possible to visualise them and study their behaviour. By inserting a luminescent protein controlled by a microscopic molecule, microRNA-9, the researchers can now distinguish the microglia and monitor their function over time in the brains of rats and mice.

It has long been known that microglia form the first line of defence of the immune system in diseases of the brain. They move quickly to the affected area and release an arsenal of molecules that protect the nerve cells and clear away damaged tissue.

New research also suggests that microglia not only guard the nerve cells but also play an important role in their basic function.

“This represents a real step forward in technological development. Now we can view microglia in a way that has not been possible before. We and our colleagues now hope to be able to use this technique to study the role of the cells in different disease models, for example Parkinson’s disease and stroke, in which microglia are believed to play an important role”, explains Johan Jakobsson.

Filed under microglia cells brain diseases drug development nerve cells neuroscience science

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Scientists Find Antibody that Transforms Bone Marrow Stem Cells Directly into Brain Cells In a serendipitous discovery, scientists at The Scripps Research Institute (TSRI) have found a way to turn bone marrow stem cells directly into brain cells. Current techniques for turning patients’ marrow cells into cells of some other desired type are relatively cumbersome, risky and effectively confined to the lab dish. The new finding points to the possibility of simpler and safer techniques. Cell therapies derived from patients’ own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection. “These results highlight the potential of antibodies as versatile manipulators of cellular functions,” said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and institute professor in the Department of Cell and Molecular Biology at TSRI, and principal investigator for the new study. “This is a far cry from the way antibodies used to be thought of—as molecules that were selected simply for binding and not function.” The researchers discovered the method, reported in the online Early Edition of the Proceedings of the National Academy of Sciences the week of April 22, 2013, while looking for lab-grown antibodies that can activate a growth-stimulating receptor on marrow cells. One antibody turned out to activate the receptor in a way that induces marrow stem cells—which normally develop into white blood cells—to become neural progenitor cells, a type of almost-mature brain cell. Nature’s Toolkit Natural antibodies are large, Y-shaped proteins produced by immune cells. Collectively, they are diverse enough to recognize about 100 billion distinct shapes on viruses, bacteria and other targets. Since the 1980s, molecular biologists have known how to produce antibodies in cell cultures in the laboratory. That has allowed them to start using this vast, target-gripping toolkit to make scientific probes, as well as diagnostics and therapies for cancer, arthritis, transplant rejection, viral infections and other diseases. In the late 1980s, Lerner and his TSRI colleagues helped invent the first techniques for generating large “libraries” of distinct antibodies and swiftly determining which of these could bind to a desired target. The anti-inflammatory antibody Humira®, now one of the world’s top-selling drugs, was discovered with the benefit of this technology. Last year, in a study spearheaded by TSRI Research Associate Hongkai Zhang, Lerner’s laboratory devised a new antibody-discovery technique—in which antibodies are produced in mammalian cells along with receptors or other target molecules of interest. The technique enables researchers to determine rapidly not just which antibodies in a library bind to a given receptor, for example, but also which ones activate the receptor and thereby alter cell function. Lab Dish in a Cell For the new study, Lerner laboratory Research Associate Jia Xie and colleagues modified the new technique so that antibody proteins produced in a given cell are physically anchored to the cell’s outer membrane, near its target receptors. “Confining an antibody’s activity to the cell in which it is produced effectively allows us to use larger antibody libraries and to screen these antibodies more quickly for a specific activity,” said Xie. With the improved technique, scientists can sift through a library of tens of millions of antibodies in a few days. In an early test, Xie used the new method to screen for antibodies that could activate the GCSF receptor, a growth-factor receptor found on bone marrow cells and other cell types. GCSF-mimicking drugs were among the first biotech bestsellers because of their ability to stimulate white blood cell growth—which counteracts the marrow-suppressing side effect of cancer chemotherapy. The team soon isolated one antibody type or “clone” that could activate the GCSF receptor and stimulate growth in test cells. The researchers then tested an unanchored, soluble version of this antibody on cultures of bone marrow stem cells from human volunteers. Whereas the GCSF protein, as expected, stimulated such stem cells to proliferate and start maturing towards adult white blood cells, the GCSF-mimicking antibody had a markedly different effect. “The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish,” remembered Xie. To Lerner, the cells were reminiscent of neural progenitor cells—which further tests for neural cell markers confirmed they were. A New Direction Changing cells of marrow lineage into cells of neural lineage—a direct identity switch termed “transdifferentiation”—just by activating a single receptor is a noteworthy achievement. Scientists do have methods for turning marrow stem cells into other adult cell types, but these methods typically require a radical and risky deprogramming of marrow cells to an embryonic-like stem-cell state, followed by a complex series of molecular nudges toward a given adult cell fate. Relatively few laboratories have reported direct transdifferentiation techniques. “As far as I know, no one has ever achieved transdifferentiation by using a single protein—a protein that potentially could be used as a therapeutic,” said Lerner. Current cell-therapy methods typically assume that a patient’s cells will be harvested, then reprogrammed and multiplied in a lab dish before being re-introduced into the patient. In principle, according to Lerner, an antibody such as the one they have discovered could be injected directly into the bloodstream of a sick patient. From the bloodstream it would find its way to the marrow, and, for example, convert some marrow stem cells into neural progenitor cells. “Those neural progenitors would infiltrate the brain, find areas of damage and help repair them,” he said. While the researchers still aren’t sure why the new antibody has such an odd effect on the GCSF receptor, they suspect it binds the receptor for longer than the natural GCSF protein can achieve, and this lengthier interaction alters the receptor’s signaling pattern. Drug-development researchers are increasingly recognizing that subtle differences in the way a cell-surface receptor is bound and activated can result in very different biological effects. That adds complexity to their task, but in principle expands the scope of what they can achieve. “If you can use the same receptor in different ways, then the potential of the genome is bigger,” said Lerner.

Scientists Find Antibody that Transforms Bone Marrow Stem Cells Directly into Brain Cells

In a serendipitous discovery, scientists at The Scripps Research Institute (TSRI) have found a way to turn bone marrow stem cells directly into brain cells.

Current techniques for turning patients’ marrow cells into cells of some other desired type are relatively cumbersome, risky and effectively confined to the lab dish. The new finding points to the possibility of simpler and safer techniques. Cell therapies derived from patients’ own cells are widely expected to be useful in treating spinal cord injuries, strokes and other conditions throughout the body, with little or no risk of immune rejection.

“These results highlight the potential of antibodies as versatile manipulators of cellular functions,” said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry and institute professor in the Department of Cell and Molecular Biology at TSRI, and principal investigator for the new study. “This is a far cry from the way antibodies used to be thought of—as molecules that were selected simply for binding and not function.”

The researchers discovered the method, reported in the online Early Edition of the Proceedings of the National Academy of Sciences the week of April 22, 2013, while looking for lab-grown antibodies that can activate a growth-stimulating receptor on marrow cells. One antibody turned out to activate the receptor in a way that induces marrow stem cells—which normally develop into white blood cells—to become neural progenitor cells, a type of almost-mature brain cell.

Nature’s Toolkit

Natural antibodies are large, Y-shaped proteins produced by immune cells. Collectively, they are diverse enough to recognize about 100 billion distinct shapes on viruses, bacteria and other targets. Since the 1980s, molecular biologists have known how to produce antibodies in cell cultures in the laboratory. That has allowed them to start using this vast, target-gripping toolkit to make scientific probes, as well as diagnostics and therapies for cancer, arthritis, transplant rejection, viral infections and other diseases.

In the late 1980s, Lerner and his TSRI colleagues helped invent the first techniques for generating large “libraries” of distinct antibodies and swiftly determining which of these could bind to a desired target. The anti-inflammatory antibody Humira®, now one of the world’s top-selling drugs, was discovered with the benefit of this technology.

Last year, in a study spearheaded by TSRI Research Associate Hongkai Zhang, Lerner’s laboratory devised a new antibody-discovery technique—in which antibodies are produced in mammalian cells along with receptors or other target molecules of interest. The technique enables researchers to determine rapidly not just which antibodies in a library bind to a given receptor, for example, but also which ones activate the receptor and thereby alter cell function.

Lab Dish in a Cell

For the new study, Lerner laboratory Research Associate Jia Xie and colleagues modified the new technique so that antibody proteins produced in a given cell are physically anchored to the cell’s outer membrane, near its target receptors. “Confining an antibody’s activity to the cell in which it is produced effectively allows us to use larger antibody libraries and to screen these antibodies more quickly for a specific activity,” said Xie. With the improved technique, scientists can sift through a library of tens of millions of antibodies in a few days.

In an early test, Xie used the new method to screen for antibodies that could activate the GCSF receptor, a growth-factor receptor found on bone marrow cells and other cell types. GCSF-mimicking drugs were among the first biotech bestsellers because of their ability to stimulate white blood cell growth—which counteracts the marrow-suppressing side effect of cancer chemotherapy.

The team soon isolated one antibody type or “clone” that could activate the GCSF receptor and stimulate growth in test cells. The researchers then tested an unanchored, soluble version of this antibody on cultures of bone marrow stem cells from human volunteers. Whereas the GCSF protein, as expected, stimulated such stem cells to proliferate and start maturing towards adult white blood cells, the GCSF-mimicking antibody had a markedly different effect.

“The cells proliferated, but also started becoming long and thin and attaching to the bottom of the dish,” remembered Xie.

To Lerner, the cells were reminiscent of neural progenitor cells—which further tests for neural cell markers confirmed they were.

A New Direction

Changing cells of marrow lineage into cells of neural lineage—a direct identity switch termed “transdifferentiation”—just by activating a single receptor is a noteworthy achievement. Scientists do have methods for turning marrow stem cells into other adult cell types, but these methods typically require a radical and risky deprogramming of marrow cells to an embryonic-like stem-cell state, followed by a complex series of molecular nudges toward a given adult cell fate. Relatively few laboratories have reported direct transdifferentiation techniques.

“As far as I know, no one has ever achieved transdifferentiation by using a single protein—a protein that potentially could be used as a therapeutic,” said Lerner.

Current cell-therapy methods typically assume that a patient’s cells will be harvested, then reprogrammed and multiplied in a lab dish before being re-introduced into the patient. In principle, according to Lerner, an antibody such as the one they have discovered could be injected directly into the bloodstream of a sick patient. From the bloodstream it would find its way to the marrow, and, for example, convert some marrow stem cells into neural progenitor cells. “Those neural progenitors would infiltrate the brain, find areas of damage and help repair them,” he said.

While the researchers still aren’t sure why the new antibody has such an odd effect on the GCSF receptor, they suspect it binds the receptor for longer than the natural GCSF protein can achieve, and this lengthier interaction alters the receptor’s signaling pattern. Drug-development researchers are increasingly recognizing that subtle differences in the way a cell-surface receptor is bound and activated can result in very different biological effects. That adds complexity to their task, but in principle expands the scope of what they can achieve. “If you can use the same receptor in different ways, then the potential of the genome is bigger,” said Lerner.

Filed under stem cells brain cells marrow cells antibodies brain drug development neuroscience science

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Research Provides Clues to Alcohol Addiction Vulnerability A Wake Forest Baptist Medical Center team studying alcohol addiction has new research that might shed light on why some drinkers are more susceptible to addiction than others. Jeff Weiner, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist, and colleagues used an animal model to look at the early stages of the addiction process and focused on how individual animals responded to alcohol. Their findings may lead not only to a better understanding of addiction, but to the development of better drugs to treat the disease as well, Weiner said. "We know that some people are much more vulnerable to alcoholism than others, just like some people have a vulnerability to cancer or heart disease," Weiner said. "We don’t have a good understanding of what causes this vulnerability, and that’s a big question. But if we can figure it out, we may be able to better identify people at risk, as well as gain important clues to help develop better drugs to treat the disease." The findings are published in the March 13 issue of the Journal of Neuroscience. Weiner, who directs the Translational Studies on Early-Life Stress and Vulnerability to Alcohol Addiction project at Wake Forest Baptist, said the study protocol was developed by the first author of the paper, Karina Abrahao, a graduate student visiting from the collaborative lab of Sougza-Formigoni, Ph.D, of the Department of Psychobiology at the Federal University of Sao Paulo, Brazil. Weiner said the study model focused on how individual animals responded to alcohol. Typically, when a drug like alcohol is given to a mouse every day, the way the animals respond increases - they become more stimulated and run around more. “In high doses, alcohol is a depressant, but in low doses, it can have a mellowing effect that results in greater activity,” he said. “Those low dose effects tend to increase over time and this increase in activity in response to repeated alcohol exposure is called locomotor sensitization.” Prior studies with other drugs, such as cocaine and amphetamine, have suggested that animals that show the greatest increases in locomotor sensitization are also the animals most likely to seek out or consume these drugs. However, the relationship between locomotor sensitization and vulnerability to high levels of alcohol drinking is not as well established, Weiner said. Usually when researchers are studying a drug, they give it to one test group while the other group gets a control solution, and then they look for behavioral differences between the two, Weiner said. But in this study, the researchers focused on individual differences in how each animal responded to the alcohol. A control group received a saline injection while another was injected with the same amount of alcohol every day for three weeks. Weiner said they used mice bred to be genetically variable like humans to make the research more relevant. "We found large variations in the development of locomotor sensitization to alcohol in these mice, with some showing robust sensitization and others showing no more of a change in locomotor activity than control mice given daily saline injections," Weiner said. "Surprisingly, when all of the alcohol-exposed mice were given an opportunity to voluntarily drink alcohol, those that had developed sensitization drank more than those that did not. In fact, the alcohol-treated mice that failed to develop sensitization drank no more alcohol than the saline-treated control group." The authors also conducted a series of neurobiological studies and discovered that mice that showed robust locomotor sensitization had deficits in a form of brain neuroplasticity - how experiences reorganize neural pathways in the brain - that has been linked with cocaine addiction in other animal models. "We found that this loss of the ability of brain cells to change the way that they communicate with each other only occurred in the animals that showed the behavioral response to alcohol," he said. "What this suggests for the first time in the alcohol addiction field is that this particular deficit may represent an important brain correlate of vulnerability to alcoholism. It’s a testable hypothesis. That’s why I think it’s an important finding."

Research Provides Clues to Alcohol Addiction Vulnerability

A Wake Forest Baptist Medical Center team studying alcohol addiction has new research that might shed light on why some drinkers are more susceptible to addiction than others.

Jeff Weiner, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist, and colleagues used an animal model to look at the early stages of the addiction process and focused on how individual animals responded to alcohol. Their findings may lead not only to a better understanding of addiction, but to the development of better drugs to treat the disease as well, Weiner said.

"We know that some people are much more vulnerable to alcoholism than others, just like some people have a vulnerability to cancer or heart disease," Weiner said. "We don’t have a good understanding of what causes this vulnerability, and that’s a big question. But if we can figure it out, we may be able to better identify people at risk, as well as gain important clues to help develop better drugs to treat the disease."

The findings are published in the March 13 issue of the Journal of Neuroscience. Weiner, who directs the Translational Studies on Early-Life Stress and Vulnerability to Alcohol Addiction project at Wake Forest Baptist, said the study protocol was developed by the first author of the paper, Karina Abrahao, a graduate student visiting from the collaborative lab of Sougza-Formigoni, Ph.D, of the Department of Psychobiology at the Federal University of Sao Paulo, Brazil.

Weiner said the study model focused on how individual animals responded to alcohol. Typically, when a drug like alcohol is given to a mouse every day, the way the animals respond increases - they become more stimulated and run around more. “In high doses, alcohol is a depressant, but in low doses, it can have a mellowing effect that results in greater activity,” he said. “Those low dose effects tend to increase over time and this increase in activity in response to repeated alcohol exposure is called locomotor sensitization.”

Prior studies with other drugs, such as cocaine and amphetamine, have suggested that animals that show the greatest increases in locomotor sensitization are also the animals most likely to seek out or consume these drugs. However, the relationship between locomotor sensitization and vulnerability to high levels of alcohol drinking is not as well established, Weiner said.

Usually when researchers are studying a drug, they give it to one test group while the other group gets a control solution, and then they look for behavioral differences between the two, Weiner said. But in this study, the researchers focused on individual differences in how each animal responded to the alcohol. A control group received a saline injection while another was injected with the same amount of alcohol every day for three weeks. Weiner said they used mice bred to be genetically variable like humans to make the research more relevant.

"We found large variations in the development of locomotor sensitization to alcohol in these mice, with some showing robust sensitization and others showing no more of a change in locomotor activity than control mice given daily saline injections," Weiner said. "Surprisingly, when all of the alcohol-exposed mice were given an opportunity to voluntarily drink alcohol, those that had developed sensitization drank more than those that did not. In fact, the alcohol-treated mice that failed to develop sensitization drank no more alcohol than the saline-treated control group."

The authors also conducted a series of neurobiological studies and discovered that mice that showed robust locomotor sensitization had deficits in a form of brain neuroplasticity - how experiences reorganize neural pathways in the brain - that has been linked with cocaine addiction in other animal models.

"We found that this loss of the ability of brain cells to change the way that they communicate with each other only occurred in the animals that showed the behavioral response to alcohol," he said. "What this suggests for the first time in the alcohol addiction field is that this particular deficit may represent an important brain correlate of vulnerability to alcoholism. It’s a testable hypothesis. That’s why I think it’s an important finding."

Filed under alcohol addiction alcohol animal model drug development neuroscience science

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