NIH INSTITUTE DIRECTORS OUTLINE PATHWAYS TO NEW THERAPIES FOR BRAIN DISEASES

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NIH INSTITUTE DIRECTORS OUTLINE PATHWAYS TO NEW THERAPIES FOR BRAIN DISEASES

ATLANTA, October 17, 2006 - National Institutes of Health (NIH) institute directors outlined today the most promising advances anticipated during the next few years for understanding and treating a wide range of neurological disorders, mental illnesses, age-related declines, vision disorders, drug abuse, and alcoholism. Many of these developments show how molecular and clinical research is gradually being translated into clinical trials addressing a wide range of possible interventions.

"The entire neuroscience community has experienced the excitement of the last decade of phenomenal progress in molecular, genetic and metabolic understanding of the normal and diseased nervous system," says Jeffrey Rothstein, MD, PhD, of the Johns Hopkins Medical Institutions who co-chairs the Society for Neuroscience's public education and communications committee. "The challenge both academic and commercial communities face is translating that data into effective therapies. To that end the principal neuroscience oriented NIH institutes have begun to organize their national priorities to include translational programs".

This research is urgent since the more than 1,000 disorders of the brain and nervous system result in more hospitalizations than any other disease group, including heart disease and cancer. Neurological illnesses affect more than 50 million Americans annually, at costs exceeding $400 billion. In addition, mental disorders, excluding drug and alcohol problems, strike 44 million adults a year at a cost of some $148 billion. The cost of drug abuse is estimated at $180.9 billion annually; alcohol abuse, $185 billion.

National Institute of Neurological Disorders and Stroke (NINDS)

"During the past few years, the NINDS has enhanced its preclinical and clinical therapy development programs to take advantage of the opportunities arising from advances in basic and clinical neuroscience," says institute director Story Landis, PhD.

A few examples of NINDS programs include the:

• Neuroprotection Exploratory Trials in Parkinson's disease (NET-PD) program which has systematically sought out, evaluated, and selected candidate drugs that might slow the progression of Parkinson's disease, then efficiently evaluated the most promising in preliminary "futility" clinical trials. It will now test the effectiveness of the best to emerge in larger clinical trials.
• Spinal Muscular Atrophy Project, a "virtual pharma" organization to develop drugs for spinal muscular atrophy. The project has systematically generated, tested in cells, and improved hundreds of compounds. The most promising candidates are moving on to further preclinical testing.
• Specialized Program of Translational Research in Acute Stroke Centers translate research findings into clinical practice for stroke. One example, now in clinical testing, is the use of ultrasound to enhance the clot busting drug tPA in the treatment of acute ischemic stroke.
• NINDS Anticonvulsant Screening Program (ASP) catalyzes academic and industry efforts to develop drugs for epilepsy by screening candidate drugs in a series of standardized cell culture and animal models. Since 1975, the ASP has screened more than 26,000 drugs from more than 400 academic and industry partners in 31 countries. More than 40 drugs from this program have entered clinical trials, including several now on the market, and 7 more that are currently in clinical development.
• NINDS led consortium of 26 laboratories which has screened a set of 1040 known drugs with laboratory tests for potential new uses against neurodegenerative diseases. One drug, ceftriaxone, is now moving testing in a clinical trial for ALS, and other are in testing in animal models.
• Study of genetics which has found, in many inherited disorders, a single defective copy of a gene from either parent produces a harmful protein that causes disease. In mouse models dominantly inherited neurological disorders, including spinocerebellar ataxia (SCA1), a form of ALS, and Huntington's disease, researchers have "silenced" the mutant gene copy while leaving the normal gene copy active. The NINDS is funding research to move this therapy toward clinical testing.

National Institute of Mental Health (NIMH)

For mental disorders, the NIMH has recognized that these disorders are brain based and has focused on neuroscience "to develop new treatments that are predictive, personalized and pre-emptive," says NIMH Director Thomas Insel, MD.

Findings from functional magnetic resonance imaging studies suggest that mental disorders involve abnormal activity in distributed brain circuits, unlike many neurological illnesses that are caused by focal brain lesions. Now the challenge is to use this new window into normal and abnormal brain activity to improve treatment. For instance, some preliminary evidence suggests that when people with depression are treated with medication, the brain circuits involved in depression begin to normalize weeks before symptomatic improvement. Other studies used regional transcranial magnetic stimulation or deep brain stimulation to alter activity in brain areas thought to be involved in depression. Imaging studies have identified abnormalities in the prefrontal cortex in people with schizophrenia, providing a locus for the cognitive deficits in this illness. While neuroimaging has not yet been helpful for predicting who will respond to treatments for cognitive deficits, new treatments for these deficits promise to boost recovery for this disabling illness.

While traditional clinical trials have focused on treatment responses in groups of patients, new studies are gaining a better understanding of individual responses, providing practical information about which therapies work best and for whom.

During the past year, NIMH has completed several practical clinical trials that are the largest and longest of their kind. With more than 10,000 patients studied at 200 sites, these "effectiveness studies" -- such as the Clinical Antipsychotic Trials of Intervention Effectiveness and Sequenced Treatment Alternatives to Relieve Depression -- were designed to examine not only changes in symptoms, but changes in functioning and to determine whether a treatment improves quality of life, care giving burden, or use of health services. DNA was collected in each of these studies, and recently, specific genetic variations identified in some study participants have been associated with response to antidepressants as well as vulnerability to serious side-effects. This pharmacogenomic approach promises to transform the treatment of mental disorders, allowing clinicians to optimize treatments based on each patient's biology.

Initiatives like the North American Prodromal Longitudinal Study (NAPLS), a consortium of NIMH-funded projects investigating the pre-psychotic phase of schizophrenia, are attempting an ambitious leap from treating mental disorders to preventing them altogether. Pre-emption invariably requires an intimate understanding of how a disease begins and progresses, the risks associated with certain symptoms, and what to target for early intervention. Already, the NAPLS has succeeded in developing the Structured Interview for Prodromal Syndromes which helps ensure consistency of methods across the different study sites. This, in turn, allows for easier data sharing and greater statistical power that comes with the larger, combined study sample. In addition, NIMH is supporting studies that show possible methods of pre-empting the serious disability caused by mental disorders. For example, several new intramural studies aim to define aspects of autism spectrum disorders that can be targeted for pre-emption.

National Institute on Aging (NIA)

Many of these same principles are being applied to the study of aging in a nation that is becoming "more old" than ever before, notes NIA Director Richard Hodes, MD. In 1900, four out of 100 Americans were older than age 65; today 12 in every 100 are older than 65; by 2050, one in every five Americans will have reached this milestone. The institute is focusing on both the factors that determine brain health and neurodegenerative disease processes.

NIA, along with the NIMH and NINDS is studying healthy brain aging through the NIH Cognitive and Emotional Health Project. A recent report from this project identified education, cardiovascular health, physical activity, psychosocial factors, and genetics as factors associated with healthy brain aging. The report calls for further study of interventions in several of these areas to determine if they help to maintain cognitive and emotional health with age. To support these efforts, the NIH Blueprint for Neuroscience Research is funding a new initiative to standardize measures and improve comparison of brain health across epidemiological studies.

NIA is also seeking to improve understanding of neurodegenerative diseases associated with aging, and significant progress has been made in understanding the basic disease processes in several disorders. For example, scientists funded by NIA recently discovered genetic mutations that cause a form of familial frontotemporal dementia, a finding that provides clues to the underlying mechanism of this devastating disease. Other recent discoveries that soluble misfolded precursors to amyloid plaques may be more toxic to neurons than amyloid plaques provide promising new drug targets for Alzheimer's disease (AD).

The institute is also moving ahead to translate basic discoveries into new diagnostic methods and clinical trials on prevention, slowing progression, and treatment strategies for AD. For example:

• Based on previous studies that linked heart disease and stroke with a higher risk for AD, researchers are conducting clinical trials to investigate whether drugs for lowering the risk for heart disease and stroke are also effective at slowing the progression of AD.
• Plaques of amyloid protein in the brain are characteristic of AD. Experiments in genetically-modified mice have demonstrated that these plaques can be removed by immunotherapy. Following suspension of the first immunotherapy clinical trial in people due to unacceptable side effects, researchers from industry and NIA have been working on a number of new approaches. An industry trial on one of them began recently, and an NIA-sponsored trial on another approach is about to start.
• Another hallmark feature of Alzheimer's disease is the brain's loss of neurons. NIA-supported research has demonstrated that nerve growth factor improves memory and prevents damage and destruction of neurons in animal models. A subsequent industry-led, early phase clinical trial of nerve growth factor in people with AD had some positive results. In a small number of patients, nerve growth factor reduced the rate of cognitive decline, increased activity in the cerebral cortex, and showed no long-term adverse effects.
• Researchers exploring links between diabetes and AD have found that insulin resistance is associated with cognitive decline. Drugs that correct or prevent insulin abnormalities are potential therapies for AD. NIA is sponsoring clinical trials on the use of such drugs, including trials on the use of the diabetes medication rosiglitazone and on the use of intranasal insulin against AD.

NIA sponsors a network of AD Research Centers at universities around the country, a genetics initiative for finding the remaining AD genes, and a drug discovery initiative to encourage more rapid translation of basic science discoveries into drugs for clinical trials. The NIH's landmark AD Neuroimaging Initiative is intended to provide the research community with the ability to image how the brain responds to investigational AD therapies in clinical trials. "Researchers are confident that progress to date offers reason to be hopeful that one day age-related neurodegenerative diseases such as AD will be conquered," says Hodes.

National Eye Institute (NEI)

Many common eye diseases and disorders result from the death of neuronal cells, according to NEI Director Paul Sieving, MD, PhD. Age-related macular degeneration (AMD) is one of the most common neurodegenerative diseases and causes severe vision impairment in older Americans. This vision loss results from death of the light-sensitive photoreceptor cells in the central region of the retina.

A major advance in eye disease research occurred this past year when scientists supported by the NEI identified subtle alterations in two genes, complement factor B and H, which account for 75 percent of the risk of developing AMD. These genes function as a part of the normal immune system's response to infection. Increasing evidence suggests that alterations in these genes are associated with chronic inflammation within the retina, perhaps instigating AMD. The identification of these genes creates the opportunity to develop therapies that address the root causes of the disease.

NEI-supported researchers also have developed a remarkable and promising gene therapy treatment that restored vision in dogs born blind with a severe neurodegenerative disease called Leber's congenital amaurosis (LCA). An initial group of dogs were given a single treatment in 2000, which resulted in a significant and long lasting recovery of vision. Subsequent experiments with many additional dogs found the treatment to work in almost every case, suggesting a very favorable rate of treatment response. LCA also occurs in young children and causes severe visual impairment at birth with nearly complete blindness at an early age. A phase one human clinical trial for LCA is planned in the coming year.

Amblyopia, also termed "lazy eye," is a condition in which vision is greatly reduced in one eye because the neural circuit that connects the eye and the brain does not work properly. Amblyopia affects 2-3 percent of children and is one of the most common causes of childhood visual impairment. Patching the better eye in very early childhood has been the mainstay of treatment. Patching relies on the plasticity of the visual cortex to force connections between the weaker eye and the brain to improve. The treatment window for amblyopia was thought to close after age 7 when the "critical period" for visual development ended and plasticity became very limited. However, recent NIH clinical trials have found that treatment for amblyopia can extend to at least age 17, thus allowing many children who were missed in early childhood a reprieve from a lifetime of visual impairment. Additional NEI studies found that patching for as little as two hours a day is effective in reversing moderate amblyopia. Previously, long patching regimens of 6 hours to 24 hours per day were used. A shorter two-hour regimen allows children to wear a patch at home, thus improving compliance. For more severe cases, 6 hours of patching with an hour of near work such as reading or coloring was found to be as effective as full-time patching. These findings suggest that neural plasticity of the brain is more sensitive and extends longer into adolescence than once thought.

The next generation of treatments for amblyopia will require an even deeper understanding of the disorder. Recent studies suggest that amblyopia tends to begin with the development of depth perception. Sophisticated imaging technologies, including functional magnetic resonance imaging, are allowing NEI-supported neuroscientists to uncover how and when the brain develops the ability to resolve disparities in the visual field that creates depth perception. Results from animal studies find that the neurons that process visual information from an eye with amblyopia respond differently to visual information than the neurons from the unaffected eye. This and other research has opened new avenues to prevent or improve therapies for the disorder.

National Institute on Drug Abuse (NIDA)

A new therapeutic paradigm has now yielded a more accurate understanding of addiction as a chronic disease of the brain, inspiring dramatic new approaches to treatment. "Whereas formerly, the focus rested on the reward system, we now know that other parts of the brain are equally important -- for example, the prefrontal cortex where decision-making capacities and emotional control reside," says NIDA Director Nora Volkow, MD. "This understanding calls for new paradigms in addiction treatment that reflect the complexity of this chronic disease."

Several of these approaches include:

Medications to diminish conditioned responses and promote new learning. The changes in the brain that result from drug abuse and lead to addiction can be thought of as aberrant learning, in which an individual becomes conditioned to compulsively seek and abuse drugs, even in the face of dire consequences. Indeed, research has shown that these conditioned responses are prominent triggers of relapse. Therefore, medications that enhance behavioral strategies to extinguish conditioned responses and facilitate the learning of new, healthful associations may offer new possibilities for addiction treatment. D-cycloserine, for example, showed encouraging results in enhancing a psychotherapeutic treatment for the pathological fear of heights. Such therapies, which target memory function, may also enhance addiction treatment.

Inhibiting stress-induced relapse. Because of the important role that stress plays as a trigger of relapse, medications that dampen the stress response could also be useful. Indeed, several compounds, known as corticotropin-releasing factor (CRF) receptor antagonists, can block the brain's stress response. In animal studies, these compounds interfere with stress-induced reinstatement of drug-seeking behavior for a number of drugs of abuse.

New medication targets. Another new area to be exploited for potential pharmacotherapies is heterodimeric receptors. Receptors -- cell surface proteins that recognize, bind, and transmit the effects of specific messenger molecules -- often work in pairs (i.e., dimers). These receptor combinations, especially those with dissimilar (i.e., heterodimer) members, can generate a broader range of neuronal responses. Targeting receptor dimers as opposed to separate receptors offers new opportunities for designing highly selective bivalent compounds able to bind to multiple receptors and dramatically expand medication options. The compound MDAN-21 represents such an exciting new development, for it engages heterodimeric opiate receptors with a powerful analgesic action without producing tolerance and physical dependence.

Neurofeedback -- using imaging technologies to train the brain. In an exciting development, scientists at Stanford University have used real-time functional brain imaging to train healthy volunteers and chronic pain patients to control their perception of pain. In this study, participants learned to regulate a brain region understood to be involved in emotional control by observing its activity on real-time brain imaging scans. The mechanisms involved in this "biofeedback" process likely engage multiple brain systems and offer new possibilities for patients to regulate their emotions -- perhaps one day enabling them to voluntarily control the disordered thinking that underlies addictions and other compulsive behaviors.

Anti-addiction immunotherapies. Unlike typical medications that treat drug addiction by targeting the drug's site of action in the brain, the goal of immunotherapies is to induce production of antibodies that target the drug itself, neutralizing it while it is still in the bloodstream and preventing its entry into the brain. A vaccine for cocaine addiction, for example, would reduce the rate and amount of cocaine uptake in the brain, diminishing its reinforcing value and preventing relapse. Antibody-based medications could also provide a rapid reversal of drug overdose effects in an emergency room setting.

NIDA will continue to pursue these innovative treatment approaches and other exciting lines of research as new findings emerge. On the horizon are individualized treatments based on a person's genetic makeup and new mechanisms for restoring an addicted person's capacity to appreciate the value of natural rewards -- all aimed at increasing a patient's chances of long-term abstinence and full recovery from this debilitating disease.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIAAA also is developing promising treatments for the nearly 18 million American adults who, in any year, struggle with alcohol abuse or alcohol dependence, notes institute director Ting-Kai Li, MD.

Naltrexone and acamprosate, which target distinct dimensions of dependence, are available in 29 countries including the United States. Naltrexone appears to reduce the rewarding aspects of drinking, particularly in genetically susceptible people. Results of a recent large study indicate that naltrexone, in combination with disease management support, can be effective in treating alcohol-dependent patients in either specialized treatment centers or primary care settings. This year, the Food and Drug Administration approved an injectable form of naltrexone, effective for 30 days, that may help to overcome problems of medication adherence. Another medication, acamprosate, appears to increase abstinence by alleviating associated dysphoric symptoms. Widely used in Europe, acamprosate was approved for use in the United States in 2004.

Although both medications demonstrated effectiveness in most clinical trials, they are not effective in all patients, says Li. This is not surprising, since alcoholism results from the interaction of genetic, individual, and environmental factors that differ from one drinker to another to produce a patient population. NIAAA research is beginning to yield heterogeneous guidance to identify the patients who are most likely to respond to a specific medication. Recent findings reveal that a polymorphism of the gene that encodes the mu-opioid receptor is associated with a positive therapeutic response to naltrexone. Acamprosate appears to be most effective in patients who have experienced physiological withdrawal symptoms.

To identify the next generation of medications, NIAAA is testing agents that target different neurobiological substrates of alcohol dependence. Preliminary human efficacy data are available for the anticonvulsant topiramate, the serotonin 5-HT3 antagonist ondansetron, and the GABAB agonist baclofen. Studies in animal models have produced additional targets for human studies that are now underway or planned for the near term. Agents in this category include cannabinoid CB1 receptor blockers and metabotropic glutamate receptor agonists, as well as agents that target drinking mediated by stress and anxiety systems through their action on corticotropin-releasing factor, neuropeptide Y, and nociceptin receptors.

Developing medications is a long, costly process with a low probability of success for any single agent. To foster more efficient, predictable drug development, NIAAA will validate preclinical models to screen novel compounds and establish a network of sites to conduct early human trials. NIAAA will encourage the pharmaceutical industry to screen proprietary compounds in the preclinical models and, when results are positive, test them in the early human trials network. These programs will help pharmaceutical companies to determine whether they should engage in the significant financial commitment for large trials and subsequent FDA consideration.

Li notes that as alcohol research continues to unravel the biological mechanisms that underlie alcohol dependence and as the drug development process becomes increasingly efficient, more -- differently targeted and synergistically acting -- medications will be available for alcoholism treatment. As a result, affected individuals and their families will be spared myriad, costly alcoholism-associated medical, psychological, social, economic, and personal problems.