mjanes 's List: Huntington's Disease

• Researchers at the California Institute of Technology (Caltech) have shown that a highly specific intrabody (an antibody fragment that works against a target inside a cell) is capable of stalling the development of Huntington's disease in a variety of mouse models.
• Gene therapy in these models successfully attenuated the symptoms of Huntington's disease and increased life span,"
• Huntington's disease is a neurodegenerative disorder with a genetic basis. The disorder has its roots in a mutation in a protein called huntingtin, or Htt. (The gene itself is also referred to as the huntingtin gene.)

• All versions of the Htt gene have repeats of a particular trio of nucleotides -- specifically, C, A, and G, which together code for the amino acid glutamine. In most people, that trio is repeated between 10 and 35 times. But in people who develop Huntington's disease, that genetic stutter goes on and on; they will have anywhere between 36 to upwards of 120 repeats.

   

  The result of all these repeats? An abnormally long version of the Htt protein, which gets chopped up into smaller, toxic pieces and accumulates in nerve cells, debilitating them.
• But the other intrabody -- called Happ1 -- was an unqualified success, restoring motor and cognitive function to the mice, and reducing neuron loss as well as toxic protein accumulation. And in one model, it increased both body weight and life span.
• Happ1 targets an amino-acid sequence unique to the Htt protein that is rich in the amino acid proline. Because of this, the action of Happ1 is expected to be extremely specific. "Our studies show that the use of intrabodies can block the parts of mutant huntingtin that cause its toxicity without affecting the wildtype, or normal, huntingtin -- or any other proteins," says Patterson. In other words, he says, this has the potential to be the kind of "silver-bullet therapy" that many medical researchers look for.

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• Investigators at Burnham Institute for Medical Research (Burnham), the University of British Columbia's Centre for Molecular Medicine and Therapeutics and the University of California, San Diego have found that normal synaptic activity in nerve cells (the electrical activity in the brain that allows nerve cells to communicate with one another) protects the brain from the misfolded proteins associated with Huntington's disease. In contrast, excessive extrasynaptic activity (aberrant electrical activity in the brain, usually not associated with communication between nerve cells) enhances the misfolded proteins' deadly effects.
• Researchers also found that the drug Memantine, which is approved to treat Alzheimer's disease, successfully treated Huntington's disease in a mouse model by preserving normal synaptic electrical activity and suppressing excessive extrasynaptic electrical activity.
• The new research shows that normal synaptic receptor activity makes nerve cells more resistant to the mutant proteins. However, excessive extrasynaptic activity contributed to increased nerve cell death. The research team found that low doses of Memantine reduce extrasynaptic activity without impairing protective synaptic activity.
• "Chronic neurodegenerative diseases like Huntington's, Alzheimer's and Parkinson's are all related to protein misfolding," said Dr. Lipton. "We show here, for the first time, that electrical activity controls protein folding, and if you have a drug that can adjust the electrical activity to the correct levels, you can protect against misfolding. Also, this verifies that appropriate electrical activity is protective, supporting the 'use it or lose it theory' of brain activity at the molecular level. For example, this finding may explain why epidemiologists have found that 'using' your brain by performing crossword puzzles and other games can stave off cognitive decline in diseases like Alzheimer's."
• "For a long time it's been known that excitotoxicity is an early marker of Huntington's disease," said Dr. Hayden. "However, now we have dissected the mechanism by which this happens, particularly focusing on NMDA receptors outside the synapse. This creates novel therapeutic opportunities to modulate these receptors with potential protective effects on nerve cells."
• A small human clinical trial of Memantine for Huntington's disease has also recently shown positive effects. Larger, international clinical trials are now being planned.

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• Huntington's disease (HD) results from genetically programmed degeneration of brain cells, called neurons, in certain areas  of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance.  HD is a familial disease, passed from parent to child through a mutation in the normal gene. Each child of an HD parent has  a 50-50 chance of inheriting the HD gene. If a child does not inherit the HD gene, he or she will not develop the disease  and cannot pass it to subsequent generations. A person who inherits the HD gene will sooner or later develop the disease.  Whether one child inherits the gene has no bearing on whether others will or will not inherit the gene. Some early symptoms  of HD are mood swings, depression, irritability or trouble driving, learning new things, remembering a fact, or making a decision.  As the disease progresses, concentration on intellectual tasks becomes increasingly difficult and the patient may have difficulty  feeding himself or herself and swallowing. The rate of disease progression and the age of onset vary from person to person.  A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD.  Presymptomic testing is available for individuals who are at risk for carrying the HD gene. In 1 to 3 percent of individuals  with HD, no family history of HD can be found.

• Huntington's disease is a devastating inherited neurodegenerative disorder that is always fatal. The disorder of the central nervous system causes progressive degeneration of cells in the brain, slowly impairing a person's ability to walk, think, talk and reason. Approximately 1 in 10,000 individuals are affected worldwide. 
  
   In the world-famous Department of Genetics at Leicester, the groups of Dr Flaviano Giorgini and Prof Charalambos Kyriacou found that by genetically targeting a particular enzyme in fruit-flies, kynurenine 3-monooxygenase or KMO, they arrested the development of the neurodegeneration associated with Huntington's disease. Furthermore by directly manipulating metabolites in the KMO cellular pathway with drugs, they could manipulate the symptoms that the flies displayed.
• The fruit-fly research at Leicester took place over three years and was funded by the Huntington's Disease Association and the CHDI Foundation, Inc. Dr Giorgini, who led the UK study, states, "This work provides the first genetic and pharmacological evidence that inhibition of a particular enzyme - KMO - is protective in an animal model of this disease, and we have also found that targeting other points in this cellular pathway can improve Huntington's disease symptoms in fruit flies. This breakthrough is important as no drugs currently exist that halt progression or delay onset of Huntington's disease. We are tremendously excited about these studies, as we hope that they will have direct ramifications for Huntington's disease patients. Our work combined with the study in our companion publication in Cell, provides important confirmation of KMO inhibition as a potential therapeutic strategy for these individuals. As many KMO inhibitors are available, and more are being developed, it is hoped that such compounds can ultimately be tested in clinical trials for this as well as other neurodegenerative disorders."

• McMaster University researchers have discovered a new drug target that may be effective at preventing the onset of Huntington's disease, working much the same way heart medications slow the progression of heart disease and reduce heart attacks.   
  
  Their landmark research discovered a family of kinase inhibitor drugs -- that all target one enzyme called IKK beta kinase -- as effective for Huntington's.   
  
  Basically, the drug restores a critical chemical change that should occur in the huntingtin protein, but does not occur in people with Huntington's disease.
• People are born with a defective gene, but symptoms usually don't appear until middle age. Early symptoms include depression and cognitive changes, with later symptoms including uncontrolled movements, clumsiness and balance problems. At some point patients may have difficulty walking, talking or swallowing. There is no specific treatment for the disease.