A Promising Development of a Gene-Silencing Tool

Sonia Vallabh, MIT and Havard Senior Group Leader, and her team were researching a type of prion disease known as fatal familial insomnia. Vallabh began her research on this prion disease after finding out she carries the disease-causing genes and that there are no current treatments, preventatives, or therapies for the fatal disease. Knowing that she would develop fatal familial insomnia in the years to come, Vallabh knew that she was racing time to develop her own treatment.

Less than two years after starting, Vallabh, Weissman, and other contributors developed gene-silencing tools that are now referred to as, "CHARMs", that can turn off the specific necessary genes to prevent prion disease proteins from being created. The CHARMs can turn off these specific genes via epigenetic editing where chemical tags are added to DNA to silence specific gene sequences. The benefits of CHARM are that the genes are kept intact so no DNA is destroyed and epigenetic editing will keep the genes suppressed with only one treatment instead of needing to constantly take pills.

The team is now working on taking these "molecular tools" and making them more versatile in their ability to provide therapy and fight against other neurodegenerative diseases. Although human trials have not taken place yet, the concept and technology have been developed and are revolutionary to the battle against neurodegenerative diseases. It is very likely that soon human trials will begin using CHARMs as a therapy and preventative measure against prion diseases. The speed at which this technology has been developed is impressive; however, passing human trials has still yet to come, which could display potential side effects that could render CHARMs ineffective.

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

https://rarediseases.info.nih.gov/diseases/6429/fatal-familial-insomnia

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003136/

The Bright Side of the Prions

        Prions, the proteins responsible for diseases like Creutzfeldt-Jakob (CJD) disease, have been becoming more and more ubiquitous in transplant recipients over the past couple of years. Prions, which are sometime referred to as proteinacious infectious particles, are misfolded protein molecules that can spread by causing other proteins to fold upon coming into contact. Scientist have studied these infectious protein molecule for sometime now, however, it was Carleton Gajdusek who originally discovered that, unlike other proteins, Prions lack the nucleic acid building blocks that are normally present in normal protein molecules. A little refresher about the structure and formations of proteins might be beneficial before continuing. As most of us already know, proteins consist of hundreds of amino acids that form long polymers chains. These long polymer chains give rise to an enormous amount of structural and functional variety. Despite their diversity, all protein molecules start with the basic amino acid sub-unit building blocks that makeup a polypeptide chain. The primary structure of a polypeptide chain undergoes a series of folding processes that eventually results in either secondary (α helix and the β pleated sheets), tertiary or quarternary structures. These long polymer chains fold into three dimensional polypeptide chains through hydrogen bonding, however, sometimes protein chains misfold during this process. Misfloded proteins are usually deactivated when this happens but when they remain active they can mutate and form Prions. According to an article posted on the NCBI website, Prions can survive in heat up to 200 °C for a couple of hours and adhere to stainless steel within minutes and remain infectious for long periods of time. The fact that Prions can survive such thorough decontamination processes means that they're easy to pass onto others. In addition to this, Prions are toxic and can cause neurodegenerative diseases but whats worse is that they're extremely resistant to disinfectants and sterilization methods. 
      This brings us to a recent concern surrounding the spread of Prions through infected organ donors. According to an article in Scientific American there is a growing epidemic of infected donors that are passing down infectious proteins. Apparently, the proteinacious infected particles have been identified in the corneas of donors who transmitted the disease on a number of occasions. According to a study posted in the scientific journal mBIO, researchers found that prion infected individual's corneas were riddled with infectious particles way before they ever exhibited symptoms. The presence of these prions found on the surface of the eye were caused by the weakening of the cornea, which allowed the infectious particles to exit through tiny neural conduits. This fortuitous observation has given doctors a way to screen for the hard to diagnose infection through methods such as electroretinograms. Because cornea transplants are becoming increasingly popular ( According to Scientific American 64,000 cornea transplants are performed each year in the US) this breakthrough arrived at a critical time and can be instrumental in developing preventative measures that stop this growing epidemic.   

Fatal Familial Insomnia

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

The disease is linked to be found in the PRNP gene, which produces a protein called prion protein, or PrP. In FFI the variant gene, the PrP that is produced develops an abnormal 3-dimensional shape that is described as misfolded. This is toxic to the body, especially to cells of the nervous system. In FFI, misfolded PrP is primarily found in the thalamus, which is a structure deep within the brain that helps to regulate many functions of the body including sleep, appetite, and body temperature. As the misfolded PrP builds up in the thalamus, it results in a progressive destruction of nerve cells (neurons), which leads to the symptoms of the disorder.

FFI is classified as a transmissible spongiform encephalopathy (TSE) or a prion disease. Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. This disorder is very rare, and it degenerates the brain. The characteristic symptom in FFI is progressive insomnia. Some people may start having insomnia suddenly and from being mild it then becomes progressively worse until an affected individual gets very little sleep. The lack of sleep leads to physical and mental deterioration and the disease ultimately progresses to coma and death.

This disease can be a product of two unaffected parents and in rare instances, a variation in the PRPN gene in individuals with FFI occurs spontaneously, without a family history of the disease. However, a person that is affected with this disease could pass on the variant gene to their offspring in an autosomal dominant manner. Unfortunately, there is no cure for this disease, but researchers are finding a way to help treat the disease.

Sources

https://rarediseases.org/rare-diseases/fatal-familial-insomnia/ Fatal Familial Insomnia

https://ghr.nlm.nih.gov/gene/PRNP PRNP gene

prion protein

Plant Memories

 

Whitehead Institute scientists have determined that a plant protein involved in the timing of flowering could in fact be a prion which is an infectious agent thought to be the cause of transmissible spongiform encephalopathies . This is the first time that a possible prion has been identified in plants, and it may play a role in a plant's 'memory' of cold exposure during winter. Viewed above, Whitehead Institute scientists inserted the Arabidopsis thaliana protein Luminidependens (LD) into yeast to determine whether it has the traits of a prion. Prion variation can occur in genetically identical yeast cells which will lead to the better understanding of this amazing theory.

This study could help us to explain the different habits and traits of plant blooming and maturation. With this knowledge, we could better understand and manipulate their "memories" in order to create plants that can bloom all year round with environments permitting. We could create plants that adapt to greenhouse life and therefore lead crops to year round harvest. No more waiting 6 months for corn to be in season again or waiting for summer to get the good prices on strawberries and blueberries. Were talking year round harvest. Hopefully these scientists at the Whitehead Institute can lead to some breakthrough evidence of these prions and can manipulate it to do some good.