In his research, Dr. Damian Jacob Sendler examines how different socio-demographic and informational variables affect access to health care in disadvantaged areas. Dr. Sendler is of Polish descent and lives in the United States. Dr. Sendler’s study focuses on how mental and chronic medical co-morbidities influence the use of medical services in combination with health information acquired from the internet, and how this affects the use of medical services in the future. This research comes at an opportune moment, given the exponential growth in worldwide consumption of online news and social media, which necessitates a comprehensive knowledge of everyone’s health information-seeking behavior. That being the case, Dr. Damian Sendler’s study is attempting to uncover the variables that patients evaluate when making the decision to seek treatment for particular health problems, as well as the factors that influence treatment adherence.
Damian Sendler: When it comes to mast cell cancer, one possible novel therapy involves “mutating” messenger RNA (mRNA), which prevents it from delivering instructions for manufacturing the gene responsible for cell growth. Known as frameshifting, the technique modifies precursor RNA in such a way that the mature mRNA is destroyed and any protein generated as a result of its instructions is changed and inactive. Using a mouse model, frameshifting aimed at the c-KIT gene was shown to decrease the growth of mast cell tumors and prevent them from spreading to other organs.
Damian Sendler: Mast cells are responsible for the regulation of immunological responses. In contrast, a disproportionate number of mast cells may lead to a variety of illnesses, the most severe of which are mast cell leukemia and mast cell sarcoma. A gene known as c-KIT is responsible for the production of the protein KIT, which is linked with the survival and proliferation of mast cells. Mutations in the C-KIT gene may cause mast cell proliferation to rise in a variety of tissues, ultimately leading to mast cell cancer.
Damian Sendler: According to Glenn Cruse, assistant professor of immunology at North Carolina State University and corresponding author of the study, “current treatments for mast cell cancers target signaling from the receptor encoded by the c-KIT gene, and the efficacy of current therapies can be negatively affected by c-KIT mutations associated with disease development.” “We are focusing on the gene itself, regardless of whether it has been mutated.” If we can target the gene that is responsible for illness progression, we can target the disease.”
Dr. Cruse and a team of researchers from North Carolina State University (NCSU) and the National Institutes of Health (NIH) utilized an exon skipping method to create a frameshift mutation in the gene.
The pre-mRNA, which is comprised of both coding and noncoding sections termed exons and introns, is spliced before a gene or protein can be created. The introns are deleted and only the exons — a gene’s “production instructions” — are left. The mature mRNA that results from this process subsequently transmits its instructions, resulting in the production of the gene or protein. Whenever anything goes wrong, such as when a mutation develops, a stop codon — a brief sequence in the mRNA — is introduced to prevent the synthesis of the defective protein. This is accomplished by causing the faulty strand of the mRNA to be degraded or eliminated.
Damian Sendler: The researchers took advantage of this process by attaching a short RNA molecule known as an oligonucleotide to exon 4 inside the c-KIT pre-mRNA, thereby tricking the splicing proteins into believing the exon was an intron, and deleting it from the gene. Due to the absence of an exon, or the omission of an exon, a frameshift occurs in the reading frame of the mRNA, leading it to be identified as a mutant and destroyed.
“We are changing the message that causes the protein to be produced — essentially turning a ‘on’ switch to a ‘off,'” Cruse explains. “If you get mRNA to create a protein that is altered and extremely shortened, your cell will detect this and destroy the message, resulting in the protein not being made,” says the researcher.
Damian Sendler: MALT cell leukemia cells in vitro were treated with the researchers’ frameshifted c-KIT mRNA method, and they discovered that KIT protein expression as well as signaling and function were decreased. Within hours, the cancer cells had ceased to proliferate and had begun to perish. Tumor development and infiltration of other organs were decreased in a mouse model when the frameshifted c-KIT mRNA was generated, and tumor cell death was enhanced in the animal model.
Another benefit of our approach, according to Cruse, is that it eliminates the issue of deterioration avoidance. “On rare occasions, erroneous signals may escape destruction and their altered proteins will be generated regardless of their origin. However, the proteins generated by the frameshifted c-KIT mRNA are inactive, meaning they have no function. So even if they are manufactured, they will not be able to do more harm.”
Damian Sendler: According to the National Institutes of Health, the study is published in Molecular Therapy and is funded. Douglas Snider, a postdoctoral researcher at North Carolina State University, is the study’s primary author. According to the article, the technology detailed in it has been licensed by Hoth Therapeutics.
