What's red hot in PD column on NPF website

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Dr. OkunJoined: 19 Jan 2007Posts: 251Location: University of Florida
Posted: Wed Nov 07, 2007 8:13 am Post subject: UPDATE: What's Red Hot in PD column on the main NPF website

I will regularly be updated this new column on the main website to keep everyone informed about what is going on in PD. Here is the latest update for our ask the doc participants. Last Updated: 11-3-07 What’s “Red Hot” in PD? Exciting Developments on the Horizon for PD Michael S. Okun, M.D. Medical Director, National Parkinson Foundation Clinicians, researchers, patients, and families have been teaming up to synergize efforts all aimed at developing better therapeutics for PD. The most common question I am asked by patients is, “what’s hot?” In response to the needs of the Parkinson community we will now regularly feature on the National Parkinson Foundation website a new column called “What’s Red Hot in PD.” I will update the webpage regularly with the help of our ask the experts (Dr.’s Fernandez, Rodriguez, and Foote), our 57 NPF Center Directors and Coordinators from around the globe, our scientific advisory board, and from you. Together we will work to provide the community with what’s exciting in PD. There are more people than ever before working on Parkinson disease (PD), and we believe there is reason for enthusiasm and hope. Surgical and Cell-Gene Therapies • Stem Cell Therapy There are two types of stem cells: embryonic and adult (not from embryos), both of which may prove exciting advancements for therapeutic development in PD. Despite the political debate surrounding the issue of stem cells, the therapy remains a promising area in research. ? What’s next? Researchers and clinicians seek to find ways to make stem cells grow into specific areas of the brain and to reconstitute damaged circuits. Additionally we must be able to switch these cells “on,” and later and perhaps selectively, to turn them off thereby preventing tumor formation. There may also exist potential to combine stem cell therapy with gene therapy. Currently most of the promising stem cell-gene therapy combination research has been limited to animals. • Gene/Viral/Factor Therapy Scientists can now load “tamed or safe” viruses carrying important genetic information, and/or growth factors and enzymes that may be able to directly target damaged brain cells or regions in patients with PD. ? What’s next? Many trials have begun worldwide, some of these trials have progressed to human studies. The most exciting recent development was the publication by Kaplitt and colleagues on a gene therapy used to change the subthalamic nucleus from an abnormally excitatory structure to an inhibitory structure. Results from the safety study were promising, and now researchers will move to examining the efficacy of this therapy. Gene therapy is also being used to deliver Amino Acid Decarboxylase (AADC), an enzyme used to enhance dopamine production; and also gene therapy can be used to deliver the growth factor Neurturin (similar to GDNF). These three gene therapies are currently undergoing human safety trials. The GDNF AMGEN trial was disappointing, however there has been debate in the field as to why the study encountered problems. There is a new factor CDNF that may soon emerge as important therapeutically, and CDNF and BDNF secreting cells represent possible neurotherapeutics for the future. • Deep Brain Surgery In the past 12 to 24 months, clinicians and researchers have continued examining a new “target” in the brainstem, the paramedian nucleus (PPN), that when stimulated, may improve the walking and balance of the Parkinson patient. This target may offer hope to patients who have falling problems—currently this symptom is treatment-refractory and perhaps the most devastating motor symptom of PD. Early studies are under way. ? What’s next? This target and other new, emerging targets can be used with already successful brain surgeries (such as deep brain stimulation) to further improve the non-motor and medication resistant symptoms of PD. Studies are underway examining the tailoring of symptoms to target (STN versus GPi DBS), and using low versus high frequency DBS (perhaps unlocking improvements in cognition, speech, and gait with low frequency rather than standard high frequency stimulation). • Genetics Researchers have applied new technologies to encode multiple genes in multiple families with Parkinsonian syndromes. The genes seem to be associated with regular PD features in many cases. ? What’s next? Scientists are now decoding genetic information to understand and unlock the potential causes of PD. Many experts believe this will be important to developing new therapeutic strategies based on uncovered genetic pathways. The LRRK2 mutation seems to be the most common mutation, and there is some enthusiasm understanding LRRK2 and the LRRK2 kinase may lead to new therapies. • RNA Technologies RNA, the single-stranded chain of nucleic acid, is responsible for translating the genetic code of DNA into proteins. Scientists have now discovered that they can manipulate and “silence” RNA by inserting sRNA (silencing RNA) into the brain to treat neurological ailments such as PD, dystonia and Huntington disease. ? Using this technology to silence RNA may represent a new therapeutic horizon for treating the disease. Researchers have developed and continue to develop novel ways to manipulate RNA technology for therapeutic benefit. Drug Therapies: • Drugs There are many drugs in development for motor and non-motor symptoms of PD. Drugs may address many of the now discovered mechanisms that may result in early or accelerated cell death in PD (oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, protein handling, apoptosis). Additionally, many researchers are looking for compounds that will slow disease progression or save brain cells (neuroprotection). Since there are so many pharmaceuticals currently in testing we would like to provide you with a brief list of drugs that NPF Directors and Coordinators are either testing, or are watching as potential red hot discoveries. Some of these have unfortunately been disappointing in early trials. Drug Therapies: Potential Neuroprotective-Neurorestorative Therapies: Rasagiline- This drug is an MAO-B inhibitor that is already approved for the symptomatic treatment of PD motor symptoms (both Rasagiline and another MAO-B inhibitor Zydis selegiline do not have an amphetamine metabolite like regular Selegline). However the largest study in early PD employing a “delayed start” design has shown the potential for disease modifying/neuroprotective effects. A study is currently underway to determine its disease-modifying potential. Coenzyme Q10- This compound stimulates the mitochondrial complex I mechanism. An early Phase II study has shown that this compound is well tolerated and that the highest dose (1200mg) had the best motor response. A larger Phase III trial will be underway shortly to investigate its neuroprotective potential. There is also concern that the formulation, and indication may influence its effectiveness. Another study has recently been disappointing and failed to show symptomatic benefit as an “add on” therapy in mid-stage disease. GPI-1485- This drug referred to as an immunophyllin was designed to be a neurorestorative drug, but was disappointing in trials. Isradipine- An antihypertensive calcium channel blocker has shown promise in animals and is being tested for safety. There is a notion that this drug may be neuroprotective and/or have symptomatic benefits. The work is based on basic science studies at Northwestern University that have show that the calcium channel is important in PD and that by blocking the “pacemaker” function of calcium channels has therapeutic promise. Parkinson patients should wait for or enroll in trials, as this finding needs to be confirmed in human studies-- there is concern over the safety (lowering blood pressure) in PD. • Pramipexole- This is an FDA approved drug for the treatment of motor symptoms in PD. One study comparing pramipexole versus levodopa in early PD has shown that patients randomized to pramipexole were less likely to be dyskinetic and develop motor fluctuations earlier in their disease course. Additionally, brain imaging done on a select portion of the patients has suggested a possible smaller decline in degeneration of dopaminergic neurons. These results need confirmation. A global study is currently underway testing its potential neuroprotective effect. Drug Therapy: Symptomatic Treatment of Motor and/or Non-Motor Symptoms: Istradefylline- This drug works as an adenosine A2 receptor antagonist. Accumulating evidence suggest that blockage of the A2A receptors reduces the excitability of the ‘indirect pathway’ of the basal ganglia circuitry (responsible for Parkinson symptoms), resulting in improvement in motor symptoms. Istradefylline has been tested globally as monotherapy in early PD, and as an adjunctive treatment to levodopa in moderate to advanced PD-- to improve “off” time. We are awaiting the results of these studies. Rotigotine- This drug is similar in structure and property to other available oral dopamine agonists, however it is novel since it is delivered by a once a day patch. This drug was recently approved for the treatment of motor symptoms in early PD. However, more studies are underway to determine other uses for this compound. Safinamide- This compund inhibits glutamate release and is also a reversible inhibitor of MAO-B. Recent studies have shown a beneficial effect on the symptoms of PD at lower doses. Tesofensine- This triple monoamine receptor inhibitor was initially felt to be promising as a treatment for the motor symptoms of PD, however clinical study results have not been encouraging. Ropinirole CR- This newly released drug is an extended release version of the dopamine agonist an d is currently sold as ropinirole (Requip). Tolcapone- This drug which was FDA approved for the treatment of wearing off lost its popularity largely because of its potential to induce liver toxicity. However, with proper monitoring, this has become less of a concern. A direct comparison is underway comparing the efficacy of tolcapone and entacapone (a class of drugs often referred to as dopamine extenders) for improving wearing off. Experts in the field largely believe tolcapone to be the more efficacious drug. Zonisamide- This medicine is currently used as an anti-seizure therapy, however a recent study has revealed it may be useful for the motor symptoms of PD. Its effect may be mediated through increasing dopamine synthesis. Levodopa Formulations- There has been interest in studying new formulations of levodopa that may improve on current limitations including the delayed “on.” Initial studies have shown ethylesters to be disappointing, however methylesters, transdermal alkylesters, and intraduodenal (small intestine) infusions remain under careful study. Leviteracetam- This is an antiseizure drug which has been considered as a potential anti-dyskinesia therapy. Initial results have shown potential poor tolerability in PD. Sarizotan- This novel 5HT1A agonist and dopamine receptor antagonist has been tested for the treatment of dyskinesias in PD. While the results of the Phase II trials were promising, the Phase III have been disappointing. CP101,606- A new drug that works as a NRB subunit selective NMDA antagonist. This drug seems to have an effect on dyskinesia but needs more study, particularly with its effects on cognition. Methylphenidate- Studies are ongoing looking at this stimulant as a treatment for gait dysfunction in PD. Other stimulants have also been of recent interest to experts in the field for fatigue, gait and other issues. Nebicapone- A new COMT inhibitor (“dopamine extender”) that is currently being tested. SLV308- This drug is a “partial” D2/D3 receptor agonist. Phase II studies have shown the drug to be just as efficacious as the “full” agonists (such as pramipexole or ropinirole) but perhaps less likely to cause side effects commonly encountered in full agonists (sleep attacks, psychosis, compulsive behavior, etc). Global studies for monotherapy in early PD and adjunctive therapy in advanced PD are currently underway to confirm preliminary results. E2007- This drug is a AMPA (works on a glutamate receptor in the brain) receptor agonist that is being looked at for wearing off and symptomatic treatment in PD. ACP-103- A 5HT2A/C Serotonin Blocker was designed to potentially target psychosis, dyskinesia and other PD symptoms. It seems to be a safe and perhaps a weakly efficacious drug for PD psychosis. Melperone- A drug that has been in Europe for a decade and has had one positive report in the literature regarding its effects on psychosis in PD. Quetiapine- An atypical antipsychotic drug that has become the first line treatment for psychosis in PD because of its ease of use and tolerability. However, there remains to be a positive double-blind placebo-controlled trial reported for this indication. More double-blind studies are underway that potentially could correct earlier methodological limitations. Cephalon 1347- Known as a JUNK inhibitor-- trials did not turn out as expected, but it may be useful for constipation. • Memantine- This is an FDA approved drug for the adjunctive treatment of moderate to advanced Alzheimer’s disease. Similar to amantadine (used for to treat dyskinesias), it works on the NMDA receptor. It is currently being tested for the treatment of both dyskinesia and dementia in PD. • Rivastigmine and other cholinersterase inhibitors (such as donepezil and galantamine). These drugs are used for the treatment of Alzheimer’s disease. Rivastigmine has been recently approved for the treatment of PD dementia. Now these drugs are also being tested for their anti-psychotic effects. • Botulinum Toxin Type B- This is a type of botulinium toxin that is currently being tested for the treatment of drooling in PD. Botulinum toxin A and other formulations also seem to be useful for this indication. • Atomoxatine- A drug that reduces norepinephrine reuptake in the brain and is now in trial for depression in PD. Additionally investigators are interested in using stimulants like this formulation to attempt to treat fatigue and gait dysfunction. • Glutathione- This “antioxidant” compound has been shown in one small open-label study to provide significant improvement in early, untreated PD when given intravenously. A recent double-blind, placebo controlled study was just completed. We await the results, and do not currently recommend its use. • Entacapone- This is an FDA approved drug as an adjunctive treatment of wearing off in PD. Trials are underway to test whether it is able to provide “continuous dopaminergic stimulation” and thereby delay the onset of dyskinesias and motor fluctuations when used early in PD. Devices and Other Approaches for Symptomatic Treatment: • Expiratory Muscle Strength Training (EMST): This device is currently in trial to improve respiratory function, swallowing and speech in PD. Early cases have been promising, but more data will be needed to evaluate its effects and in which patients it may be useful. • BIG and LOUD Multidisciplinary Approach- Used for treatment of speech and gait disorders, and is currently under investigation. It is a combination of LSVT and physical therapy, and issues of efficacy and what may be the best maintenance therapy remain to be worked out. • Exercise and Weight Training for PD: Recently a collaborative group of investigators have come together to begin sharing information and designing trials to address exercise and other physical activities in PD. Several trials are underway and there has been early planning for potential future neuroprotective studies. • Treatment of the Masked Face: The NIH is currently sponsoring a trial of a device that can be used to potentially treat the masked face in PD. • Formation of Multi Interdisciplinary Care and Outreach Teams Over recent years there has been a paradigm shift in the way that care and outreach is being delivered to the Parkinson patient. The Allied Team Training for Parkinson (ATTP) and Parkinson centers of excellence, have been developed by NPF as a multi-disciplinary model for comprehensive care and outreach for PD sufferers. ? What’s next? To date, many health professionals from medical institutions around the planet have completed the ATTP training program, and there is a growing movement to multiply interdisciplinary care and outreach centers across the globe—efforts by multiple foundations and research centers through the NIH. Watch List- Future Research which may be Translated from the Basic Science Laboratories There are several areas of interest we are watching carefully to see if there may be a transition into new therapeutic strategies: • Inhibition of a protein called alpha-synuclein synthesis or aggregation. There are several potential approaches here including small molecule aggregation inhibitors, siRNA suppression of alpha-synuclein synthesis, and/or an alpha-synuclein vaccine. There are challenges to these therapies especially because the aggregates are located inside the cells and may be difficult to reach. • Proteasome Modifiers- This approach aims to alter protein processing in the PD brain . There are modulators of proteasome function, moderators of protein folding, pharmacological chaperone molecules (e.g. isofagomine), and there has been interest in induction of a group of molecules called heat shock proteins. • Mitochondrial Disease Approaches- PD patients have abnormalities in intracellular areas called mitochondria (energy producing part of the cell). Therapies like CoQ may be useful in early disease, but another study was less promising in mid-stage disease. More studies are needed and perhaps investigators will be able to use PINK1 genetic forms of PD-- PINK1 kinase activators may help us understand and target mitochondrial function. • The LRRK2 genetic form of PD has an increase in an enzyme called a kinase. LRRK2 kinase inhibitors could be potential therapeutics. • There are additional brain targets that scientists are interested in exploiting for therapeutic benefit and these include: Dopamine (D1) agonists, Dopamine (D3) agonists, Glutamatergic Pathways (Ionotropic channels- NMDA/AMPA/KAINATE and Metabotropic Receptors). • There are a group of compounds called Sirtuin 2 Inhibitors that may rescue alpha-synuclein mediated toxicity. • A group of scientists are interested in neuroinflammation as a potential cause of PD and they are looking carefully TNF-alpha, PPAR, MTOR inhibitors, and Rapamycin as potential future neurotherapeutics._________________Michael S. Okun, M.D.
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Posted: Wed Nov 07, 2007 2:59 pm Post subject: Whats Red Hot in PD Research

Thank you for an incredibly uplifting posting. It makes me hopeful that I just might live long enough to see a cure !!!
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