In recent years, messenger RNA, DNAs close cousin in lifes complex process of going from a string of genetic blueprints to fully functioning organism, has received intense scrutiny in the scientific and medical community for the role it can play in creating next-generation vaccines, cancer treatments, and stem cell therapies addressing a myriad of previously incurable diseases. The previously obscure topic of mRNA became a nearly universal household utterance following the rush to discover a type of vaccine that could prevent COVID-19 related fatalities. The scientific communitys herculean effort did result in Pfizers mRNA COVID-19 vaccine, and products with similar mechanisms of action closely follow from other US and global pharmaceutical companies.
An international research team led by Professor Katsura Asano of Hiroshima Universitys Graduate School of Integrated Sciences for Life in Japan, and also of Kansas State University in the US, set out to find new ways to artificially induce mRNA to respond in ways that could eventually lead to therapeutic outcomes, expanding on the success of the mRNA-based COVID-19 vaccines and opening up new possibilities across a host of possible genetic therapies.
Asano and his research team paid attention to a biochemical process termed chemical modification that adds a chemical mark to RNA bases, corresponding to a genetic letter of lifes blueprint, and identified such chemical marks that both speed up and slow down action in the beginnings of the chemical zippers involved in generating gene-specified proteins. They published their findings in Science Advances.
In animals, including humans, mRNA is called to action in the protein production process with a signal called the AUG Start Codon, a universal code for the genetic zipper of RNA. The compound that AUG makes up is an amino acid called methionine, one of the twenty building blocks of protein molecules. Other RNA codons such as GUG (amino acid Valine), UUG (amino acid Leucine), and CUG (also Leucine) are generally considered non-start codons, meaning theyre less likely to represent the beginning of a gene translation. Instead, they appear in the middle of protein coding region that is meant to unzip the genetic blueprint and produce a given protein.
Few other codons than AUG are known to be able to activate mRNA in the way AUG does. But in setting out to change that, Asano and his team set out to test common RNA chemical modifications, evaluating their effects on different types of rare start codons initiating the translation process. To do so, they used their previous discovery that GUG, UUG, and CUG codons that are different by one letter from AUG, are converted to a reasonably strong start codon specifying methionine through attaching the optimum RNA sequence for initiating their translation event in animals. Their study design pitted a dozen RNA sequences, derived from these sequences, for expressing green fluorescent proteins through various non-AUG start codons at various efficiencies. To accurately evaluate GFP expression, they used a technique called flow cytometry to measure fluorescence from ~10,000 cells per attached RNA sequence and start codon. In this way, they compared translation efficiencies between natural RNA and chemically modified RNA.
They found common trends in altering translation efficiencies when a certain non-AUG start codon received a certain chemical mark. A remarkable discovery, they reported, was the ability of U-to-Psi (pseudouridine) conversion to dramatically increase initiation potentials of CUG, GUG and UUG start codons (and more satisfyingly no affect on AUG). Chemical modification of non-AUG start codons can greatly alter initiation frequencies from these codons, Asano said. Computer simulation played a key role in understanding the mechanism leading to these effects. mRNA translation from non-AUG start codons is an old but new concept. These start codons were used in prokaryotes [bacteria] but our research takes the concept a big step further by highlighting the possibilities of doing so in eukaryotes, including humans.
Asano hopes the medical industry will take note of this new body of data and continue to conduct further research into how to use chemical modified RNA for generating synthetic expression switchesin such a way to stimulate translation activity in a highly targeted way in humans and animals. I am hoping that the companies making mRNA vaccines will use our findings, he said. For example, they could use UUG start codon and chemically modify mRNA by 1m Psi, as Pfizer did with their COVID-19 vaccine. They will allow strong expression of the antigen from the start codon and yet avoid protein expression from cDNA made and integrated into genome by chance.
Asano explained further that so far, no significant risks related to long-term use of various mRNA vaccines have been identified. But there is a small chance that vaccines against retroviruses make vaccine cDNA when the patient encounters these viruses during immunization. If this integrates into the patients genome, the antigen may be expressed in a way that attenuates vaccine production for boosting, he said. But beyond that, the concept is so easy and adds no extra cost. So we hope these techniques are adopted.
- This press release was originally published on the Hiroshima University website
More:
Chemical Markers That May Unlock Future Therapeutic Uses of mRNA - Lab Manager Magazine
- Human cells in a rat's brain could shed light on autism and ADHD - Kansas Public Radio - October 13th, 2022
- California is poised to phase out sales of new gas-powered cars - Kansas Public Radio - August 30th, 2022
- Doctors Transplant Kidneys to Children Without Need for Immune ... - July 11th, 2022
- The Future of Parkinson Disease Therapies and the Challenges With Stem Cell Therapies - Neurology Live - June 22nd, 2022
- Jayhawks shine at 2022 Capitol Graduate Research Summit | The University of Kansas - KU Today - April 19th, 2022
- Four researchers named recipients of the University Scholarly Achievement Award | The University of Kansas - KU Today - March 25th, 2022
- COVID-19 directly damages, creates scar tissue on the kidneys, study finds - WDAF FOX4 Kansas City - January 5th, 2022
- The controversy being created about the origins of the virus that causes COVID-19 - Frontline - July 6th, 2021
- Kelly lauds $21 billion state budget bill, vetoes $500,000 ... - June 6th, 2021
- [Full text] Binding of the SARS-CoV-2 Spike Protein | HMER - Dove Medical Press - April 15th, 2021
- IN8bio announces first-in-human Phase 1 trial Update from The University of Kansas Cancer Center using INB-100, IN8bio's Gamma Delta T-cell product... - December 4th, 2020
- Incysus Therapeutics Announces Name Change to IN8bio, Inc. - GlobeNewswire - August 28th, 2020
- Seeing through a forest of SCN2A gene variation - SFARI News - February 20th, 2020
- FHSU partners with Be the Match for bone marrow registry event - hays Post - February 20th, 2020
- Trial cancer treatment in Wichita - KAKE - December 2nd, 2019
- Infanticide: Live Organ Harvesting Commonplace in US Abortion Mills - Church Militant - October 17th, 2019
- Kansas Regenerative Stem Cell Seminar - Stem Cell Centers ... - September 10th, 2019
- Stem Cell Procedures | Motus Biologics of Kansas City - September 9th, 2019
- Stem Cell Therapy in Kansas City- Rejuvenate KC | Stem ... - April 26th, 2019
- Hip Stem Cell Treatment | Motus Biologics in Kansas City - January 23rd, 2019
- About Stem Cell Therapy - Kansas Regenerative Medicine - November 29th, 2018
- Stem Cell Therapy in Wichita, Kansas | Joint Pain Relief ... - October 6th, 2018
- Kansas Stem Cell Center Close To First Clinical Trial | KCUR - August 27th, 2018
- Knee Stem Cell Treatments in Kansas City | Motus Biologics - August 2nd, 2018
- Stem cells relieve chronic pain in Kansas City, MO - July 30th, 2018
- Adult Stem Cell Therapy 101, MSCTC - University of Kansas ... - July 7th, 2018
- Stem cells or Knee surgery - Kansas Regenerative Medicine - June 28th, 2018
- Future Fertility Fix? Egg-Producing Stem Cells Found in ... - October 14th, 2017
- Regenexx Kansas City | Helping your body heal itself - September 24th, 2017
- Feared Zika virus kills brain cancer stem cells, new research shows - Kansas City Star - September 8th, 2017
- Shawnee Woman Was Among First In The World To Undergo New FDA-Approved Cancer Therapy - KCUR - September 8th, 2017
- Paralyzed after pool accident, student heads back to college - Kansas City Star - August 30th, 2017
- About Us, Midwest Stem Cell Therapy Center - KUMC - August 30th, 2017
- Join Jon Kempin, LA Galaxy Foundation and Gift of Life Marrow Registry for Kick Blood Cancer on August 13 - LA Galaxy - August 12th, 2017
- Regenerative Medicine Market in the US - Forecasts, Segmentation, and Opportunity Assessment by Technavio - Business Wire (press release) - August 8th, 2017
- International Space Station's Crew Restored to Six People - Kansas City infoZine - July 30th, 2017
- Scientists build DNA from scratch to alter life's blueprint - Kansas City Star - July 30th, 2017
- Stem Cell Collection - University of Kansas Hospital - October 30th, 2016
- Stem Cell Therapy - North Kansas City Hospital, Kansas ... - October 14th, 2016
- Stem Cell Therapy | Kansas RMC - August 3rd, 2016
- Kansas to Build First US Stem Cell Research Center | CorCell - August 3rd, 2016
- Stem cell program - University of Kansas Medical Center - August 3rd, 2016
- Stem Cell Therapy for Urological Issues | Kansas RMC - July 29th, 2016
- Kansas Regenerative Medicine Center - October 19th, 2015
- Egg Stem Cells - MIT Technology Review - September 27th, 2015
- Doctors in Kansas who treat or diagnose Stem Cell Transplant - August 1st, 2015
- Stem Cells for Paralysis: First of Its Kind Study - April 7th, 2015
- Topeka retailer honored as 'business of the year' - March 7th, 2015
- Saint Lukes Mid America Heart Institute Offers Tips & Treatments For Heart Failure Awareness Week 2015 - February 10th, 2015
- Exploring Stem Cell Therapy for Cerebral Palsy | See the Seitz - December 12th, 2014
- Therapeutic potential of human induced pluripotent stem ... - November 5th, 2014
- Advisory Board, Midwest Stem Cell Therapy Center - November 2nd, 2014
- Myocardial infarction and stem cells - National Center for ... - October 31st, 2014
- Precise and programmable biological circuits - October 24th, 2014
- Stowers Researchers Reveal Molecular Competition Drives ... - September 6th, 2014
- Midwest Stem Cell Therapy Center, University of Kansas ... - September 1st, 2014
- Stem Cell History | A History of Stem Cell Research - August 23rd, 2014
- Kansas City MO Resources - Stem Cells: Get Facts on Uses ... - August 22nd, 2014