CRISPR Reverses Huntington’s Disease in Mice | GEN

  Huntington disease is an inherited, progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). [NIH]
The potential of genome-editing techniques, such as CRISPR/Cas9, to alleviate disease burden has ignited the imagination for thousands of researchers looking for new therapeutic strategies. Scientists were very quickly able to show that this gene-altering technique could eliminate disease-causing mutations within a variety of tissues in vitro. More recently, CRISPR is being positioned to help treat patients directly, with clinical trials in humans already under way in China and soon to begin in the U.S. Yet, no current clinical trials feature drugs made using the technique for the treatment of neurodegenerative diseases.

Now, a group of investigators led by scientists at Emory University is hoping to open up new avenues of neurodegenerative research and rapidly move toward human trials after the release of their new findings. The research team showed that the CRISPR/Cas9 system could snip part of a gene that produces toxic protein aggregates in the brains of 9-month-old mice used as a model for Huntington’s disease. Moreover, the scientists noted that when they looked at the brain region where the vector was applied, some weeks later, the aggregated proteins had almost disappeared. Amazingly, the motor abilities of the mice had improved, although not to the level of control mice.            

Findings from the new study were published today in the Journal of Clinical Investigation through an article entitled, “CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease.”"



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PLOS ONE: Huntingtons Disease Mice Infected with Toxoplasma gondii Demonstrate Early Kynurenine Pathway Activation, Altered CD8+ T-Cell Responses, and Premature Mortality

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-repeat expansion in the huntingtin protein. Activation of the kynurenine pathway of tryptophan degradation is implicated in the pathogenesis of HD. Indoleamine-2,3-dioxygenase (IDO) catalyzes the oxidation of tryptophan to kynurenine, the first step in this pathway. The prevalent, neuroinvasive protozoal pathogen Toxoplasma gondii (T. gondii) results in clinically silent life-long infection in immune-competent individuals. T. gondii infection results in activation of IDO which provides some protection against the parasite by depleting tryptophan which the parasite cannot synthesize. The kynurenine pathway may therefore represent a point of synergism between HD and T. gondii infection. We show here that IDO activity is elevated at least four-fold in frontal cortex and striata of non-infected N171-82Q HD mice at 14-weeks corresponding to early–advanced HD. T. gondii infection at 5 weeks resulted in elevation of cortical IDO activity in HD mice. HD-infected mice died significantly earlier than wild-type infected and HD control mice. Prior to death, infected HD mice demonstrated decreased CD8+ T-lymphocyte proliferation in brain and spleen compared to wild-type infected mice. We demonstrate for the first time that HD mice have an altered response to an infectious agent that is characterized by premature mortality, altered immune responses and early activation of IDO. Findings are relevant to understanding how T. gondii infection may interact with pathways mediating neurodegeneration in HD.

Huntington's disease: Therapeutic potential of triheptanoin confirmed -- ScienceDaily

"The therapeutic potential of triheptanoin in 10 patients with Huntington's disease has been demonstrated by researchers. Huntington's disease is a genetic disease; mutation of the gene encoding the huntingtin protein results in a progressive degeneration of the neurons, especially in regions of the brain involved in the control of movement, thereby causing serious neurological, motor, cognitive and psychiatric problems. Weight loss is also observed in patients at an early stage in the disease, despite normal or even increased food intake. These two observations (degeneration of neurons and loss of weight) led the researchers to propose the hypothesis that an energy deficit in these patients might play an important role in the onset and progression of the disease symptoms."

A new cellular garbage control pathway with relevance for human neurodegenerative diseases: Max Planck Institute of Biochemistry |

Several human neurodegenerative diseases, including Alzheimer’s,
Parkinson’s and Huntington’s disease but also ageing, are linked to an
accumulation of abnormal and aggregated proteins in cells. Cellular
“garbage” of this type can be removed from cells by sweeping them to a
cellular recycling station known as the lysosome. Scientists at the Max
Planck Institute of Biochemistry in Martinsried, Germany, now discovered
a new family of helper proteins that recognize labeled cellular protein
waste and guide them efficiently to the lysosome for destruction and
subsequent recycling into their reusable compounds. The results of this
study, now published in the journal Cell, are crucial for our
understanding how cells remove cellular waste and will open new avenues
for studies aimed to fight neurodegenerative diseases.

In Huntington's patients, healthy tissue grafted to the brain also develops the disease - Medical News Today

A recent study published in Annals of Neurology reports that healthy human tissue grafted to the brains of patients with Huntington's disease in the hopes of treating the neurological disorder also developed signs of the illness, several years after the graft. This discovery will have profound implications on our understanding of the disease and how to treat it, and may also lead to the development of new therapies for neurodegenerative disorders.



Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann Neurol 2014 May 6. doi: 10.1002/ana.24174

Animal models reveal promising approach to slow brain degeneration in Huntington's disease - Medical News Today

Research presented by Dr. Lynn Raymond, from the University of British
Columbia, shows that blocking a specific class of glutamate receptors,
called extrasynaptic NMDA receptors, (with memantine )can improve motor learning and
coordination, and prevent cell death in animal models of Huntington
disease. As Huntington disease is an inherited condition that can be
detected decades before any clinical symptoms are seen in humans, a
better understanding of the earliest changes in brain cell (neuronal)
function, and the molecular pathways underlying those changes, could
lead to preventive treatments that delay the onset of symptoms and
neurodegeneration.

Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington/'s disease : Nature : Nature Publishing Group

Huntington’s disease is an autosomal dominant disease associated with a
mutation in the gene encoding huntingtin (Htt) leading to expanded
polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress,
neurotoxicity, and motor and behavioural changes.
Huntington’s disease is characterized by highly selective and profound
damage to the corpus striatum, which regulates motor function. Striatal
selectivity of Huntington’s disease may reflect the striatally selective
small G protein Rhes binding to mHtt and enhancing its neurotoxicity.
Specific molecular mechanisms by which mHtt elicits neurodegeneration
have been hard to determine. Here we show a major depletion of
cystathionine γ-lyase (CSE), the biosynthetic
enzyme for cysteine, in Huntington’s disease tissues, which may mediate
Huntington’s disease pathophysiology. The defect occurs at the
transcriptional level and seems to reflect influences of mHtt on
specificity protein 1, a transcriptional activator for CSE. Consistent
with the notion of loss of CSE as a pathogenic mechanism,
supplementation with cysteine reverses abnormalities in cultures of
Huntington’s disease tissues and in intact mouse models of Huntington’s
disease, suggesting therapeutic potential.
(Cysteine is also necessary for glutathione synthesis )

Protein clusters implicated in neurodegenerative diseases actually serve to protect brain cells

In two ground-breaking studies, published in the journals PLOS ONE and Nature Communications, Prof. Lederkremer and his team demonstrated that protein clusters are not the cause of toxicity in Huntington's disease.
On the contrary, these aggregates actually serve as a defense mechanism
for "stressed" brain cells. Conducted on tissue cultures using
cutting-edge microscopic technology, their studies identified a
different causative agent—the "stress response" of affected brain cells.

Prof. Lederkremer and his team chose to examine the effect of protein
aggregates in the pathology of Huntington's disease because its genetic
cause is well-known, unlike those of other neurodegenerative diseases,
such as Parkinson's, whose origins remain less clear.


"What we found in this study—a surprise, although we suspected it—was
that damage to the cells, the cell 'stress' that leads to death of
cells, appeared well before the protein aggregates did," said Prof.
Lederkremer. "And even more surprising, when the aggregates finally
appeared, the stress was reduced, in some cases even stopping. The
actual process of forming an aggregate was protective, isolating and
segregating the problematic proteins. This explains why in autopsies of
people who died of Huntington's and other diseases like Alzheimer's or
old age, the protein aggregates in the brains were all quite similar,
reflecting no specific disease link."

Brain degeneration in Huntington's disease caused by amino acid deficiency

Working with genetically engineered mice, Johns Hopkins neuroscientists
report they have identified what they believe is the cause of the vast
disintegration of a part of the brain called the corpus striatum in
rodents and people with Huntington's disease: loss of the ability to
make the amino acid cysteine. They also found that disease progression
slowed in mice that were fed a diet rich in cysteine, which is found in
foods such as wheat germ and whey protein.

Cystathionine gamma lyase (CSE) synthesizes cysteine in mouse and human brain tissues
and this group found found considerably less CSE in Huntington's diseased tissues. All people
carry some normal huntingtin protein made by the Huntington's disease
gene, although the protein's function remains elusive. But people with
Huntington's disease also carry mutant huntingtin proteins. Snyder and
his team saw that the mutant proteins were attaching themselves to a
crucial protein responsible for turning the CSE gene on or off, which
ultimately led the diseased rodent and human brain tissues to be
deprived of cysteine.

Huntington disease prevention trial shows creatine safe, suggests slowing of progression

Among the ways that the mutated form of the huntingtin protein damages brain cells is by interfering with cellular energy production, leading to a depletion of ATP, the molecule that powers most biological processes. Known to help restore ATP and maintain cellular energy, creatine is being investigated to treat a number of neurological conditions – including Parkinson disease, amyotrophic lateral sclerosis and spinal cord injury. Studies in mouse models of HD showed that creatine raises brain ATP levels and protects against neurodegeneration. Previous clinical trials of creatine in symptomatic HD patients have been limited in scale, involved daily doses of 10 grams or less, and did not provide evidence of potential efficacy. Based on the results of a pilot study at MGH that evaluated doses as high as 40 grams, participants in the current study received doses of up to 30 grams daily.

Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding

Huntington disease (HD) is a progressive neurodegenerative disorder caused by dominant polyglutamine (polyQ) expansion within the N terminus of huntingtin (Htt) protein. Abnormal metal accumulation in the striatum of HD patients has been reported for many years, but a causative relationship has not yet been established. Furthermore, if metal is indeed involved in HD, the underlying mechanism needs to be explored. Here using a Drosophila model of HD, wherein Htt exon1 with expanded polyQ (Htt exon1-polyQ) is introduced, we show that altered expression of genes involved in copper metabolism significantly modulates the HD progression. Intervention of dietary copper levels also modifies HD phenotypes in the fly. Copper reduction to a large extent decreases the level of oligomerized and aggregated Htt. Strikingly, substitution of two potential copper-binding residues of Htt, Met8 and His82, completely dissociates the copper-intensifying toxicity of Htt exon1-polyQ. Our results therefore indicate HD entails two levels of toxicity: the copper-facilitated protein aggregation as conferred by a direct copper binding in the exon1 and the copper-independent polyQ toxicity. The existence of these two parallel pathways converging into Htt toxicity also suggests that an ideal HD therapy would be a multipronged approach that takes both these actions into consideration.

Possible role for Huntington's gene discovered

MIT biological engineers have found that the protein encoded by this mutant gene alters patterns of chemical modifications of DNA. This type of modification, known as methylation, controls whether genes are turned on or off at any given time. The mutant form of this protein, dubbed "huntingtin," appears to specifically target genes involved in brain cell function. Disruptions in the expression of these genes could account for the neurodegenerative symptoms seen in Huntington's disease, including early changes in cognition, says Ernest Fraenkel, an associate professor of biological engineering at MIT.

Read more at: http://medicalxpress.com/news/2013-01-role-huntington-gene.html#jCp

Hundreds Of Potential Drug Targets For Huntington's Disease Identified By Genome-Scale Study

Scientists searching for ways to develop treatments for Huntington's disease (HD) just got a roadmap that could dramatically speed their discovery process. Researchers at the Buck Institute have used RNA interference (RNAi) technology to identify hundreds of "druggable" molecular targets linked to the toxicity associated with the devastating, ultimately fatal disease. The results from this unprecedented genome-scale screen in a human cell model of HD are published in the journal PLOS Genetics. MNT

JCI - Mutant huntingtin impairs immune cell migration in Huntington disease

In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

Promising therapy developed for Huntington's disease

Science Daily: The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell's power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's.

Toxic protein build-up in blood shines light on Huntington's disease

A new light-based technique for measuring levels of the toxic protein that causes Huntington's disease (HD) has been used to demonstrate that the protein builds up gradually in blood cells. Published today in the Journal of Clinical Investigation, the findings shed light on how the protein causes damage in the brain, and could be useful for monitoring the progression of HD, or testing new drugs aimed at suppressing production of the harmful protein.

Read more at: http://medicalxpress.com/news/2012-09-toxic-protein-build-up-blood-huntington.html#jCp

Huntington's Disease Symptoms May Be Reversed By Proposed Drug: Single Treatment Produces Long-Term Improvement In Animal Models

Don W. Cleveland, PhD, professor and chair of the UC San Diego Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, and colleagues infused mouse and primate models of Huntington's disease with one-time injections of an identified DNA drug based on antisense oligonucleotides (ASOs). These ASOs selectively bind to and destroy the mutant gene's molecular instructions for making the toxic huntingtin protein.

The treatment produced rapid results. Treated animals began moving better within one month and achieved normal motor function within two. More remarkably, the benefits persisted, lasting nine months, well after the drug had disappeared and production of the toxic proteins had resumed.

Having Huntington's disease or other 'polyQ' diseases protects against cancer, suggesting common genetic mechanism

Having Huntington's disease or other diseases known as polyglutamine (polyQ) diseases reduces a person's risk of getting cancer, suggesting a common genetic mechanism, concludes an Article published Online First by The Lancet Oncology. The study is by Dr Jianguang Ji, Lund University, and Skåne University Hospital, Malmö, Sweden, and colleagues.

U of A medical researchers discover 'very promising' treatment for Huntington disease

The molecule used (the ganglioside GM1) in the lab tests at the U of A was produced both naturally and synthetically through chemical production. This same molecule has been used in clinical trials for the treatment of Parkinson's and other neurodegenerative diseases, so using this molecule to treat patients with Huntington disease in a small first stage clinical trial could happen relatively quickly. Details are still being worked out about where the trial would take place, but researchers are hoping it will be at the U of A and are in discussions with a University of Alberta Hospital neurologist.

RIKEN | Press Release | 2011 | New study uncovers how brain cells degrade dangerous protein aggregates

Researchers at the RIKEN Brain Science Institute (BSI) have discovered a key mechanism responsible for selectively degrading aggregates of ubiquitinated proteins from the cell. Their findings indicate that the capture and removal of such aggregates is mediated by the phosphorylation of a protein called p62, opening the door to new avenues for treating neurodegenerative diseases such as Huntington's disease and Alzheimer's disease.