Therapeutic strategies to strengthen antioxidant defences could help to prevent the progression of Huntington’s Disease. This is the suggestion from the results of the first ever trial on human samples carried out by researchers at the University of Lleida. The results have been published in the latest issue of Free Radical Biology & Medicine magazine.

A study carried out by Catalan researchers shows that oxidative stress and damage to certain macromolecules are involved in the progression of Huntington’s Disease (HD), which is characterised by psychiatric and cognitive disturbance, involuntary movements (chorea) and dementia.

The research was carried out using human brain samples obtained post mortem from people affected by HD, which were compared with samples from control patients (C) who had died from unrelated illnesses or other causes. The two cerebral areas most affected by this illness the striate cortex and cortex ?” were studied.

The samples, which were provided by the tissue bank at the University of Barcelona’s Institute of Neuropathology, were divided into HD-C group pairs based on gender, age, and the length of time after death before the tissue had been removed.

“Bidimensional electrophoresis techniques were used to compare the differences between the proteins present in the brains of the sick people and those of the controls,” said Elisa Cabiscol, professor of biochemistry at the University of Lleida, and one of the report’s authors. “The results showed that more than half of these were enzymes related to antioxidant defence systems.”

This study, which used human samples for the first time and was funded by Spain’s Consolider-Ingenio 2010 Programme, found that the brain tissue from people suffering from HD had elevated levels of proteins that eliminate reactive oxygen species (ROS), or free radicals, as they are more commonly known.

“There is a situation we call oxidative stress in the brains of these patients, and as a result the neurones (and other cells in the brain, such as the glia cells) attempt to defend themselves by increasing their antioxidant defences,” said Cabiscol.

In normal conditions, the balance between ROS generation and antioxidant systems allows cells to function correctly. However, in a situation of oxidative stress, ROS generation exceeds the cells’ defence capacity, causing changes in the cells that ultimately cause them to die.

“Our proteomic study has made clear how important a role oxidative stress plays in this illness, calling for the use of therapeutic strategies that boost antioxidant defences or prevent the formation of ROS, on order to try to halt or slow down the progression of this devastating disease,” added the researcher.

Huntington’s Disease

HD is caused by degeneration of cells in the brain, the neurones, as a result of genetic changes. The symptoms of this disease that runs in families first become apparent in middle age, and it progresses over 15 to 20 years before leading to an inevitable death. Both the speed at which the disease progresses and the age of onset varies from one person to another.

Mutation on the /htt/ gene generates an abnormal protein (huntingtin), which has a ‘polyglutamine tail’. These polyglutamines eventually cause the protein to form aggregates. “What we still don’t understand is the function of this protein, and how the presence of these aggregates causes the neurones in certain areas of the brain to malfunction and die,” said Cabiscol.

Statistical estimates show that one in every 10,000 people suffers from HD, translating into more than 4,000 sufferers in a country such as Spain. However, Montse Torrecilla, secretary of the Spanish Huntington’s Chorea Association (ACHE), says there is a lack of real data on the number of patients. “This is a complex issue, because one has to bear in mind the number of misdiagnoses and people who hide, or are still not aware of, their illness,” she said.

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The New York Times on Monday examined how “dermatology is fast becoming a two-tier business in which higher-paying customers” seeking cosmetic procedures “often receive greater pampering” than “medical patients for whom health insurance pays fixed reimbursement rates.”

According to the Times, dermatology is one of the specialties in which patients “are not only willing to pay for quality-of-life treatments that may not be covered by insurance,” but also are willing to pay “much more for such treatments than insurers would pay for a medical procedure that takes a similar amount of time.” Health insurers typically reimburse a physician $60 to $90 for a visit that includes a full-body skin cancer check, which takes about 10 minutes. Dermatologists might receive $500, paid on the day of treatment, for a Botox injection to the forehead that takes 10 minutes.

The Times reports that some dermatologists have separate waiting and examination rooms for cosmetic and medical patients. In addition, some dermatologists offer additional services — such as valet parking — for cosmetic patients. Donald Richey, a California dermatologist, said, “Cosmetic patients have a much more private environment than general medical patients because they expect that,” and physicians “are a little bit more sensitive to their needs.” Richey said his efforts to cater to cosmetic patients do not hinder the level of care for medical patients and noted that he keeps walk-in times available to see medical patients.

A study published last year in the Journal of the American Academy of Dermatology found that dermatologists in 11 U.S. cities and one county offered appointments to patients seeking Botox sooner than patients inquiring about a changing mole, which is a possible sign of skin cancer. The study also found some dermatologists are staffing nurse practitioners and physicians’ assistants, known as physician extenders, to primarily see medical patients. Mixed Message?
According to the Times, as “dermatologists are trying to advance the idea of a national skin cancer epidemic, such a two-tier system is raising concerns that the coddling of beauty patients may divert attention from skin diseases.” Several people interviewed by the Times said dermatologists they saw for medical reasons treated them as potential cosmetic patients.

Davis Pariser, a dermatologist and president-elect of the American Academy of Dermatology, said, “The message is that the cosmetic patient is more important than the medical patient, and that’s not a good message.” Julie Cantor, a lawyer and medical school graduate who teaches a medical ethics course at the University of California-Los Angeles, said, “If you really started treating patients differently based on their ability to pay out of pocket, that’s a real problem,” adding, “People who want their wrinkles fixed to go to a wedding should not be treated better than those who have psoriasis”.

Reprinted with kind permission from http://www.kaisernetwork.org

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A treatment that prolongs survival in mice with prion disease has been found in research led by Dr Giovanna Mallucci at the Medical Research Council Prion Unit at UCL (University College London). Examples of prion diseases include vCJD and kuru in humans and BSE in cows. The results are published in PNAS.

Dr Mallucci and colleagues used a harmless form of virus carrying a specific strand of RNA to block production of prion protein in brain cells in mice with prion disease.

In prion diseases, a naturally occurring protein in the brain, known as prion protein (PrP), changes its normal shape when it comes into contact with misshapen versions of the same protein ‘prions’. These abnormally shaped proteins build up in the brain and are infectious: once they start to accumulate they convert more and more of the normal PrP into the abnormal form, also known as PrPSc. This conversion process is associated with malfunction of brain cells, eventually leading to their death. These changes cause the symptoms of prion disease.

Past research at the Prion Unit and elsewhere has shown that normal PrP is a valid therapeutic target for prion disease, because if naturally occurring PrP is absent, prions cannot replicate and the PrPSc form cannot accumulate. Dr Mallucci’s group set the scene for this new treatment in the past by showing that mice genetically engineered to stop making normal PrP recovered from prion disease when normal PrP production was switched off in infected mice.

Now the team has turned this approach into a treatment that does not depend on genetic changes in the whole animal. They have shown that by using a modified virus expressing a small sequence of RNA (shRNA) that binds to the PrP RNA in brain cells, the production of PrP can be blocked. The virally-expressed shRNA interrupts the normal process of translation of RNA into protein molecules in a process known as RNA interference.

The team gave a single one-off injection of the virus into a specific brain region in mice that had early prion infection. Blocking PrP production in this way in mice with established prion disease was found to have two effects. Firstly, the mice given the virus carrying RNA lived on average 19% longer than mice given a virus with no RNA and 24% longer than mice given no treatment at all. Secondly, the treatment prevented the onset of behavioural problems associated with early prion disease, and showed protection against degeneration of brain tissue and the loss of neurones.

Commenting on the significance of the finding Dr Mallucci said:

”The results are exciting because they have proved that tackling PrP even in a very focal way is beneficial in prion disease, protecting brain cells and extending survival in this model. Clearly, there is an issue with delivery of such treatments to a much larger organ such as the human brain and we don’t know how much brain tissue would need to be targeted. These injections target tiny volumes of brain tissue. Getting the virus to a much larger brain area is a major goal for all gene therapy for neurodegenerative diseases. These results help us to answer other questions using this approach, which may help us to understand how to tackle these diseases with other forms of treatment also. Using this approach we can explore whether there are critical areas to be targeted in prion disease, how much of the brain needs to be targeted and understand the timing of such treatments.”

”This does not represent a realistic treatment for human patients, but it backs approaches of all types aimed at taking out normal PrP and should help us understand the timing and extent of delivery needed for effective treatments in future,” Dr Mallucci concluded.

Original research paper: Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease by White et al is published in the journal PNAS.

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The Michael J. Fox Foundation for Parkinson’s Research has announced approximately $2.4 million in total funding to nine research teams under its Target Validation initiative. This annual MJFF program provides intellectual and financial resources to help push potential PD drug targets forward toward clinical trials and ultimately the nearly five million Parkinson’s patients worldwide.

“The discovery of a new potential therapeutic target generates great excitement among patients and researchers,” said Katie Hood, CEO of The Michael J. Fox Foundation. “But to attract an industry sponsor with the resources and expertise to chaperone it through optimization, preclinical work and ultimately clinical testing, that target needs a critical mass of evidence behind it, demonstrating that it is involved in the disease and that manipulating it impacts symptoms or progression. MJFF’s Target Validation program helps accumulate this evidence, reducing the risk of investment for industry and building the case for prioritization of the most promising targets in the pipeline.”

Target validation is an essential and historically underresourced phase of drug development in which researchers work to determine whether a molecule or mechanism of interest is a true drug target. While researchers have continued to identify novel targets in recent years through genetic, biochemical and epidemiological studies, a lack of funding for validation studies has long been a major roadblock to the efficient translation of these discoveries into practical therapies that benefit people living with PD.

Projects funded in this cohort of Target Validation awardees fall into three categories: targets for therapies to alleviate symptoms of PD; approaches focused on dyskinesias, the excessive, uncontrollable movements brought on by long-term dopamine replacement therapy; and targets with potential to slow or stop progression of Parkinson’s, something no currently approved treatment has been proven to do.

Two investigators will be continuing projects initiated under previous MJFF programs, reflecting the Foundation’s desire to keep promising work moving forward quickly. Stephen F. Traynelis, PhD, of Emory University was funded under MJFF’s Community Fast Track 2005 initiative to screen small-molecule compound libraries for molecules that inhibit a certain type of brain receptor - called the NR2D-containing NMDA receptor - in the basal ganglia, a part of the brain involved in Parkinson’s disease. His new award will allow him to take this work to the next level, testing these molecules to see if they can reduce PD-like symptoms in rodent models. Kalipada Pahan, PhD, of Rush University is investigating a protein called NF-kB, which is involved in the inflammation process that some believe might trigger or promote continued loss of cells in the Parkinson’s brain. Dr. Pahan has already shown that delivering specific inhibitors against NF-kB is neuroprotective in a rodent model of Parkinson’s. He will now work to confirm his results in a non-human primate model of PD as the next step toward possible clinical trials.

Other investigators will be looking at various targets for possible relevance to therapeutic strategies for PD. Danny G. Winder, PhD, and Roger J. Colbran, PhD, both at Vanderbilt University and Ann M. Graybiel, PhD, at the Massachusetts Institute of Technology are each investigating new targets for possible roles in the development of dyskinesias. To identify strategies that could protect from loss of brain cells in PD, investigators Pamela J. McLean, PhD, of Massachusetts General Hospital (Harvard University), Malu G. Tansey, PhD, of University of Texas Southwestern Medical Center and Benjamin Wolozin, MD PhD, of Boston University School of Medicine will manipulate various proteins in PD animal models. Finally, Yvette F. Tache, PhD, of the University of California, Los Angeles, has developed a possible rodent model of PD-associated gastrointestinal (GI) dysfunction. She will use the model to test drugs that can alleviate this ‘non-motor’ symptom, which might also allow for better delivery of existing drugs such as levodopa that must pass through the GI tract to enter the bloodstream.

The following is a complete list of researchers who were awarded grants under Target Validation 2007. For grant abstracts and researcher bios, visit http://www.michaeljfox.org.

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