Treatment for Fatal Prion Diseases: The Promise of CHARMs in Gene Silencing

Prions diseases occur when a protein regularly found in the body is misfolded, causing illness. This misfolding leads to brain damage alongside other symptoms, which take years to develop. Once a person is symptomatic, the disease rapidly progresses in the body, leading to death. Researchers at the Broad Institute of MIT and Harvard and researchers from the Whitehead Institute for Biomedical Research have developed promising new therapies for fatal prion diseases. The collaboration between the two programs led to the development of a new set of molecular tools known as CHARMs (Coupled Histone tail for Autoinhibition Release of Methyltransferase), which silences the gene that causes the production of the disease-causing proteins, alongside stopping the production of more of these genes, CHARMs can also stop already generated prion protein genes. One of the researchers, Sonia Vallabh, pushes the urgency of this project as she suffers from an increased likelihood of developing fatal familial insomnia, another form of prion disease. While initially starting in the law industry, Vallabh and her husband shifted their careers toward biomedical research after discovering a lack of treatments for these conditions. Their work doesn't only focus on treating prion disease, but they continue to research other disorders that cause the loss of neurons in the brain caused by toxic protein accumulation.


The CHARMs technology uses epigenetic editing, which uses an epigenome, a make-up of chemical compounds and proteins that can attach to DNA and allow actions such as turning genes on or off, which specifically targets the prion protein gene, quickly silencing them and preventing any more production of misfolded proteins which may have led to a prions diseases. Tests conducted on mice confirm that these tools can remove up to 80% of prion proteins found in the brain, a significant increase from the 21% removal rate used with past techniques to relieve symptoms. The researchers saw challenges when creating CHARMs, especially in trying to ensure that the components used were non-toxic, alongside being able to target the prion gene without any side effects. Using the machinery built into the cells, the researchers could silence the gene, minimizing the potential toxicity. While the development of CHARMs is still too unsafe for humans, the astonishing rate of development shows hope for those who suffer from prion diseases and other diseases caused by protein misfolding.


While new tools to treat prion diseases are being developed at astonishing rates, it will still be a while before CHARMs can be used to treat humans with prion disease. When the time comes when CHARMs are safe to use, they will revolutionize the medical field, helping prevent the decline in mental capacity due to misfolding. I find this article very reliving as while prion disease doesn't run in my family, Alzheimer's does, and both are similar to where misfolding can lead to a decline in cognitive functions. While not the same, if the development goes well for CHARMs to help treat prion disease, it could be used as a stepping stone to preventing Alzheimer's as well.


https://news.mit.edu/2024/charmed-collaboration-creates-therapy-candidate-fatal-prion-diseases-0627

https://www.usatoday.com/story/news/health/2024/06/27/stop-dementia-delay-brain-disease-medical-research/74190613007/

The Dutch Hunger Winter: Starvation and its Effect on Genes

In September 1944, allied forces failed and all trains coming into the Netherlands came to holt. The Nazis planned to punish the Dutch people by blocking all food supplies going into the Netherlands thus, plunging much of the country into famine. By the time Holland was liberated in May 1945, more than 20,000 people had died of starvation. Pregnant people who survived the famine were uniquely affected in that their children would be influenced by the famine for the rest of their lives. When these children became adults they were heavier than average and as they became middle-aged they had higher levels of triglycerides and LDL cholesterol. Conditions such as diabetes, schizophrenia, and obesity were common and they as reached old age it was found that their mortality increased by 10% once past the age of 68.

Dr. Heijmans, a geneticist and Dr. Lumey, an epidemiologist published a paper with a possible answer. Their study suggests that the Dutch Hunger Winter silenced certain genes in the unborn children and they've stayed quiet since. Certain genes are active in some cells and some are quiet and this is set since birth unless something acts upon them, for example a virus; the study of this gene control is called epigenetics. Researchers have found that silenced genes have a collection of methyl groups near by. The researcher speculate that these methyl groups are affected by prenatal conditions thus, can affect the activity of genes. As terrible as the Dutch Hunger Winter was there is a silver lining. This silver lining has allowed researchers to study a unique health outcome that may help us better understand gene silencing and how a pregnant person's environment can affect their unborn child.
https://www.nytimes.com/2018/01/31/science/dutch-famine-genes.html
https://www.verzetsmuseum.org/museum/en/tweede-wereldoorlog/kingdomofthenetherlands/thenetherlands/thenetherlands,june_1944_-_may_1945/the_hunger_winter

Trial Starts for New Huntington's Drug

Landmark Huntington's Trial Starts



"The first drug that can potentially correct the underlying defect that causes Huntington's disease has been taken by patients in a clinical trial. The disease is caused by the brain producing a mutant protein called huntingtin which damages and ultimately kills off brain cells. As Huntington's progresses it leads to uncontrolled movements, behavior changes and poor cognition. Life expectancy after diagnosis can be as short as 10 years."

The drug used in the clinical trial is known as a gene silencer. It works by targeting mRNA (messenger RNA) strands which contain the instructions for the mutated protein. The drug was manufactured to bind to the mRNA and neutralize it. The drug will be administered via injections into the spinal cord over the course of four months and then the patients will be observed for an additional three months.

This is an amazing step forward in the field of medicine. Not only is Huntington's incurable to date, but the medications for it only treat the symptoms while doing nothing to slow the damage. The article goes on to discuss the safety precautions the clinicians are taking while administering the drug. Hopefully, the results for the human trials are as promising as the pre-clinical work.

Mother's Diet and Child's Gene Expression

It has already been shown that the diet of female animals upon conception can have obvious effects on their offspring. For example, studies have shown that a female mouse's diet can permanently effect the coat color of her offspring. It has always been suspected that their must be similar correlations between a mothers diet and the genes of her offspring in humans. Researchers with MRC International Nutrition Group have shown that a human mother's diet can have significant effects on the "silencing" of her child's genes.

There is a strong dependence on the consumption of grown foods in Gambia. There is also distinct rainy and dry seasons which have extreme effects on the growth of these foods, meaning the diets of Gambia's people changes with the seasons. Researchers sampled 167 pregnant women (84 of which conceived at peak of rainy season and 83 conceived at peak of dry season) and tested nutrient levels in their blood as well as examining the genes of the child. It was found that those mothers who conceived at the peak of the dry season consistently had children with less methyl groups (which are used for the silencing of certain genes) than those who had conceived at the peak of the rainy season. The inability of silencing certain genes can have serious repercussions such as proneness to disease. Good nutrients at the time of conception is vital for gene expression and to help avoid some diseases. This is a revolutionary breakthrough in that scientists can now continue testing and begin on helping mothers to be to create prime diets for optimal methyl group production.

Article Link: http://www.sciencedaily.com/releases/2014/04/140429125733.htm
Related Article: http://www.genengnews.com/gen-news-highlights/mother-s-diet-has-life-long-effects-on-child-s-gene-function/81249809/

Aging Erodes Genetic Control, but That's Flexible

     Undergraduate researchers at Brown University have recently confirmed a hypothesized age defect in flies, one which was previously only known to happen in yeast. Researchers had found that in yeast, age led to the degredation of gene supression, which contributed to many problems common to advanced age (due to the need for harmful genes to be surpressed). Using reporter genes to track levels of silencing, the Brown researchers were able to repeat this phenomenon is fruit flies. Using this new knowledge, they then tried several different "anti-aging" techniques to see if they restored levels of gene silencing found in the younger flies. Of these methods, severe calorie restriction was found to be the most useful.
     While this finding doesn't necessarily prove that the same process occurs in humans, it certainly posits that this may be the case. While further study is necessary, having an aging indicator like gene silencing would allow scientists to find out which methods of youth restoration are most effective.

     This article hit home for me. Anti-aging science has always been a topic of interest, and one that is of vital importance and urgency (not getting any younger...). While the findings here are small, they are definitely an important step towards anti-aging technology of the future.

http://www.sciencedaily.com/releases/2013/11/131120143752.htm
http://venturebeat.com/2013/11/20/calico-enlists-a-genetics-a-team-for-its-mysterious-anti-aging-venture/

Brain Cancer Gene Silenced in Mice by Experimental Drug

            According to an article on USNews.com, researchers have created an experimental drug that is able to silence a gene related to a deadly brain cancer in mice.  In basic terms, silencing a gene means turning off a gene and its expression.  The experimental drug was created through the use of nanotechnology by 2 scientists from Northwestern University named Chad Mirkin and Alexander Stegh.  It acts upon the gene Bcl2L12, which is responsible for the creation of proteins that prevents the killing of cancer cells.  The type of incurable brain cancer that this new drug works against is called glioblastoma multiforme and it is the cause of 13,000 deaths in America each year.  People who are unfortunate to become diagnosed with this terrible cancer usually have an average survival rate of 14 to 16 months and about 16,000 cases are diagnosed each year.  This drug has caused remarkable results in mice that have glioblastoma multiforme.  Since the drug is so small, it can easily cross the blood-brain barrier and get to the brain tumors.  Then, this drug is able to get inside the brain tumors and turn off the gene so that its expression is terminated.  The drug was administered to mice through intravenous injection and it resulted in the mice having a 20% longer survival rate as well as causing the size of the cancerous tumors to become three to four times smaller.  The next step for the two scientists is to begin testing the experimental drug in clinical trials.

            After doing a little bit of research on glioblastoma multiforme, I came to realize how deadly this brain cancer is and can’t imagine how those who are diagnosed with it must feel.  Even though drugs and new medicine prove to be successful in animals, it does not mean that the treatment will be as successful in humans. However, this new drug provides hope to those who are suffering from this terrible cancer.  Hopefully, the drug is successful in clinical trials because it could help so many people.  By utilizing this drug along with other cancer treatments, it may be possible to cure people of glioblastoma multiforme.  Possibly, the nanotechnology used in creating this drug can be utilized with developing treatments for other cancers like lung, breast, and gastric.  This technology can be also applied to shutting off genes that cause other diseases.  With the knowledge that scientists have about cancers like glioblastoma multiforme, it is amazing how advanced the technology is that is used in creating treatments.  I believe that with the advanced technology that we have today, we are getting ever closer to curing cancer and this article proves we are heading in the right direction.  

 

Scientists 'Silence' Aggressive Brain Cancer Gene in Mice

Test Mice 

Glioblastoma multiforme

 

                A new experimental drug has been found to turn off a gene that is connected to an aggressive and incurable type of brain cancer in mice. Glioblastoma multiforme is a brain cancer that is responsible for 13,000 American deaths a year. The new experimental is uses nanotechnology, which is small enough to advance through the blood-brain barrier to make contract with the brain tumors. This nanotechnology will target the cancer causing gene in the cells and shut them off; this means that the cancer causing genes were silenced.

Gene Silencing

  

               According to the study in, Science Translational Medicine, the mice that were used in these experiments were given the new drug intravenously. The results showed that the mice lived 20 percent longer and their tumors shrank three to four times in size. This had shown amazing progression towards ending this terrible disease. This opens up many doors to different therapy resistances. Many experimental drugs that are used against Glioblastoma fail in clinical trials. The next step is to test this experimental drug in clinical trials, though many results in animal studies are different when used in human studies. Hopefully, silencing these genes and eliminating them from the scenario will allow more treatments to be effective.  

                This disease is the source of thousands of people yearly. I find it amazing that we have come up with such technology that allows us to shut down cancer causing genes. By shutting down these genes, we give ourselves the time to do more research on the cancer itself to see if there are ways to eliminate it completely. This can also open up more research into silencing other genes for other diseases. Nanotechnology can be the beginning of a new era of disease control. 

http://health.usnews.com/health-news/news/articles/2013/10/30/scientists-silence-aggressive-brain-cancer-gene-in-mice

http://www.ncbi.nlm.nih.gov/genome/probe/doc/ApplSilencing.shtml

Gene Silencing Strategy Step Towards Chromosome Therapy

         Jeanne Lawrence, Ph.D., Professor of Cell & Developmental Biology at the University Massachusetts Medical School, provided evidence that the genetic defect causing trisomy 21 can be suppressed in laboratory stem cell cultures.  Trisomy 21 is also known as Down syndrome.  It is a genetic condition where an individual has 47 chromosomes rather than 46, the extra being located at the 21st chromosome.    

     With the use of an advanced genome editing tool extra chromosomes are neutralized by silencing the genes on the extra chromosome.  This is done on laboratory cultures from cells from individuals that have down syndrome.  Trisomic stem cells that were muted were compared to identical trisomic cells that were untreated.  Through comparative observations, researchers were able to identify defects in the rapid growth and specialization of untreated nervous system cells.  These observed defects are regressed in which the extra chromosome is muted.  The silencing of trisomy 21 by manipulation is a great step forward for the development of chromosome therapy not only for chromosome 21 but genome wide.

     The possibility that this one discovery can lead to many different paths for the discovery of new cures and use in other therapies and solutions is great! By finding new techniques for silencing abnormal chromosomes, the development of chromosome

therapy can lead to cures for other chromosomal disorders that may be fatal.  Hopefully future advancements using this discovery will not surpass the point where it is used for superficial reasons, such as creating the perfect/ideal child!

http://www.medicalnewstoday.com/releases/267815.php

http://en.wikipedia.org/wiki/Down_syndrome