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NeuroNews: Top Ten Therapeutic Trends By Gail Schechter, Ph.D. The field of neurology is progressing rapidly and intelligently on several fronts. Presented in this summary are the top ten trends in neurotherapeutics selected from the more than 1,000 presentations at the recent American Academy of Neurology (AAN) 56th annual meeting. Targeting Alzheimer's Disease (AD) Researchers have mounted a huge push to develop novel disease-modifying agents to prevent or slow the progression of AD, since the currently approved anticholinesterase inhibitors and memantine only target clinical symptoms. Delaying disease progression by 5 years would lead to a 50% decline in AD patients, and delaying it by 10 years would virtually wipe out AD, as older people would die of other causes. Several different therapeutic modalities targeting the pathology of AD are in the pipeline, including: Anti-amyloid drugs; Anti-inflammatory agents (COX-2 inhibitors); Antioxidants; Immunotherapies; Neurotrophic factors; Secretase inhibitors; and Statins (Leon Thal [University of California, San Diego] recipient of the Potamkin Prize for outstanding research, and Steven DeKosky [University of Pittsburgh, PA]). Preventing MCI Conversion Currently, there is intense focus on the early diagnosis of mild cognitive impairment (MCI) for the purpose of preventing progression to Alzheimer's disease, which occurs in 12%-15% (per year) of individuals with MCI. The continuum from normal memory, to MCI, to dementia may span a decade or more, so there is ample opportunity to slow disease progression if we could develop better interventions. To date, treatments have not successfully reduced the rate of conversion, but clinical trials to evaluate cholinesterase inhibitors, vitamin E, and COX-2 inhibitors are currently underway. Estrogen is Out Estrogen was previously thought to play a positive role in cognitive functioning. Despite strong epidemiological evidence suggesting a protective effect of hormone replacement therapy against AD in post-menopausal woman, estrogen has not been proven effective in double-blind, placebo-controlled studies. In fact, recent results suggested a slight excess of dementia and other morbidities in the estrogen-treated groups, leading to the cessation of several major clinical trials and the abandonment of this therapeutic avenue in AD. Statins are In Neurology has borrowed promising treatments from cardiology. There is growing evidence that cholesterol may play a role in the pathogenesis of AD and that statins may be protective. A tripartite of cardiovascular risk factors--hypercholesteremia, hypertension, and increased homocysteine--are potential new therapeutic targets. Homocysteine levels can be reduced with folate and vitamins B6 and B12. Large, double-blind, placebo-controlled studies of statins in AD are in progress. Newly published results (announced as this article went to press) also point to the use of statins in multiple sclerosis and show data revealing plaque reduction. Neurotrophic Factors Re-Emerge New results from a nerve growth factor (NGF) gene therapy trial provided preliminary evidence of efficacy in a small number of AD patients in an uncontrolled Phase I clinical trial. Fibroblasts derived from each patient's skin were genetically modified to produce NGF and then implanted into cholinergic brain regions known to degenerate in AD. Results showed a reduced rate of cognitive decline, increased rate of metabolic activity in key brain regions assessed using positron emission tomography (PET), and NGF activity and cell growth in the brain of one autopsy patient (presented by Mark Tuszynski, University of California, San Diego). Ceregene, which has exclusive worldwide rights to the UCSD technology used in the study, plans to conduct a Phase I/II study in AD to evaluate a non patient-specific product that is comprised of an adeno-associated viral (AAV) gene delivery system carrying the NGF gene. Another positive report on neurotrophic factors suggested that human recombinant glial cell-line derived neurotrophic factor (GDNF) pumped directly into the brain improved clinical symptoms in patients with severe Parkinson's disease. GDNF is a promising therapeutic strategy because of its potent trophic effects on dopaminergic neurons that degenerate in Parkinson's disease. In this study, 5 patients received human recombinant GDNF (Amgen, Thousand Oaks, CA) by direct, continuous infusion over the course of two years, which resulted in clinical motor improvement and an increase in localized PET 18F-dopa uptake, suggesting dopaminergic upregulation (Gary Hotton, Imperial College and Hammersmith Hospital, London). Stem Cells--Not Ready for Prime Time Countless patients and scientists have pinned their hopes on stem cells as a potential new therapeutic venue to treat a host of neurodegenerative diseases. In spite of substantial progress in many areas of stem cell science, more basic research is needed to work out the underlying mechanisms. A new study reported that cells taken from adult human bone marrow and cultured with growth factors could be converted into neuronal cells that meet the criteria for transplantation into the brain (Alexander Storch, University of Ulm, Germany). Future use of converted adult stem cells would circumvent the ethical and technical issues related to the use of embryonic stem cells, since bone marrow cells from an individual could be extracted, converted and then transplanted into the brain. Seeking Biomarkers The quest continues to identify biomarkers for many neurological disorders. Especially in AD, the establishment of valid ante-mortem neurobiological markers would be valuable for improving early and accurate diagnosis, selecting patients for specific treatments, and monitoring therapeutic effects over time. The pursuit of biomarkers is being fueled by increased recognition of a prolonged, preclinical, prodromal disease phase, coupled with potential new disease-modifying agents on the therapeutic horizon. Existing AD biomarkers in cerebral spinal fluid (CSF), particularly Abeta and tau, are being refined, and new tests in blood are being researched. In addition, promising MRI markers to quantify early structural (and functional) deficits in AD are under investigation. For example, brain volume loss observed prior to diagnosis may identify patients who are destined to develop dementia. A related report found that FDG-PET imaging was a promising approach to early diagnosis of cancer-related neurological disorders. In that study, PET scanning successfully identified a high proportion of paraneoplastic neurological disorders that were undetectable by alternative diagnostic methods (Steven Allder, Royal Hallamshire Hospital, Sheffield, UK). Nutritional Supplements: Yes, No, Maybe So There is a potential role for vitamins--such as vitamin E, vitamin C, folate, and iron--in AD, which currently is being sorted out in clinical trials. In particular, the evaluation of antioxidants, e.g., vitamins E and C in combination, is still ongoing. A new report suggests that the popular supplement coenzyme Q 10 (CoQ10), which previously was recognized as a potential therapy for several neurodegenerative disorders, may also help prevent migraine. Migraine patients who took 100 mg three times a day of CoQ10, which acts as the body's energy producer, had fewer attacks in three months than those who took a placebo (Peter Sandor, University Hospitals, Zurich). Personalized Medicine in Neurology Rapid progress in gene profiling has implications for the individualized treatment of neurological disorders. A recent study in multiple sclerosis suggests that there are four distinct patterns of antibody responses that might be helpful in selecting patient-specific treatments. In Alzheimer's disease, APOE-4 is widely recognized to increase the risk of developing the disease, whereas APOE-2 is thought to be protective. A new study in Parkinson's disease shows that APOE-2 may increase the risk of Parkinson's disease, indicating that APOE may have varying effects in different neurodegenerative diseases (Xuemei Huang, University of North Carolina, Chapel Hill). Gene expression will undoubtedly play an increasingly important role in tailoring patient-specific therapies in the near future. Time to Wake Up to Sleep Sleep medicine, both to treat insomnia and to promote wakefulness, is gaining momentum as a fertile therapeutic area for development. It turns out that a large number of individuals want to increase their sleep quality and quantity, while others want to enhance wakefulness. The emphasis on alertness has recently leaped to the forefront as the Department of Defense seeks new treatments to maintain alertness during wartime. In addition, there are several specific neurological disorders related to sleep that require therapeutic attention, including: restless legs syndrome, REM sleep behavior disorder; and narcolepsy (Michael Silber, Rochester, MN). Testing of existing medications such as clonazepam, melatonin, and other agents is underway in these disorders. -------------------------------------------------------------------------------- This coverage was provided by Gail Schechter, Ph.D., President, BioIntelligence, a consulting group specializing in CNS product development and grant writing. She may be contacted in San Francisco, CA, via e-mail at Brains@BioIntelligence.com. Source: D&MD To view and purchase D&MD reports click here! |
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