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Scientists develop novel mRNA delivery method using extracellular vesicles

A team of researchers led by The University of Texas MD Anderson Cancer Center has developed a novel delivery system for messenger RNA (mRNA) using extracellular…

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A team of researchers led by The University of Texas MD Anderson Cancer Center has developed a novel delivery system for messenger RNA (mRNA) using extracellular vesicles (EVs). The new technique has the potential to overcome many of the delivery hurdles faced by other promising mRNA therapies.

Credit: The University of Texas MD Anderson Cancer Center

A team of researchers led by The University of Texas MD Anderson Cancer Center has developed a novel delivery system for messenger RNA (mRNA) using extracellular vesicles (EVs). The new technique has the potential to overcome many of the delivery hurdles faced by other promising mRNA therapies.

In the study, published today in Nature Biomedical Engineering, the researchers use EV-encapsulated mRNA to initiate and sustain collagen production for several months in the cells of photoaged skin in laboratory models. It is the first therapy to demonstrate this ability and represents a proof-of-concept for deploying the EV mRNA therapy.

“This is an entirely new modality for delivering mRNA,” said corresponding author Betty Kim, M.D., Ph.D., professor of Neurosurgery. “We used it in our study to initiate collagen production in cells, but it has the potential to be a delivery system for a number of mRNA therapies that currently have no good method for being delivered.”

The genetic code for building specific proteins is contained in mRNA but delivering mRNA within the body is one of the largest hurdles facing clinical applications of many mRNA-based therapies.

The current COVID-19 vaccines, which marked the first widespread use of mRNA therapy, use lipid nanoparticles for delivery, and the other primary delivery systems for genetic materials so far have been viral based. However, each of these approaches comes with certain limitations and challenges.

Extracellular vesicles are small structures created by cells that transport biomolecules and nucleic acids in the body. These naturally occurring particles can be modified to carry mRNAs, which gives them the benefit of innate biocompatibility without triggering a strong immune response, allowing them to be administered multiple times. Additionally, their size allows them to carry even the largest human genes and proteins.

In the current study, the research team used EV mRNA therapy to deliver COL1A1 mRNA, which encodes the collagen protein, into the skin cells of a laboratory model that mimics aging-damaged skin in humans. The EV mRNA was administered using a microneedle delivery system via a patch applied to the skin. This single injection improved collagen production and reduced wrinkle formation in the targeted area for two months.

While initiating collagen production in cells is a noteworthy achievement on its own, Kim said, this study opens the door for further evaluation of EV mRNA therapy as a viable platform for mRNA delivery.

“mRNA therapies have the potential to address a number of health issues, from protein loss as we age to hereditary disorders where beneficial genes or proteins are missing,” Kim said. “There is even the potential for delivering tumor-suppressing mRNA as a cancer therapy, so finding a new avenue to deliver mRNA is exciting. There is still work to be done to bring this to the clinic, but these early results are promising.”

This research was supported by an institutional fund from MD Anderson. A full list of collaborating authors and their disclosures can be found in the full paper here.


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Another airline is making lounge fees more expensive

Qantas Airways is increasing the price of accessing its network of lounges by as much as 17%.

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Over the last two years, multiple airlines have dealt with crowding in their lounges. While they are designed as a luxury experience for a small subset of travelers, high numbers of people taking a trip post-pandemic as well as the different ways they are able to gain access through status or certain credit cards made it difficult for some airlines to keep up with keeping foods stocked, common areas clean and having enough staff to serve bar drinks at the rate that customers expect them.

In the fall of 2023, Delta Air Lines  (DAL)  caught serious traveler outcry after announcing that it was cracking down on crowding by raising how much one needs to spend for lounge access and limiting the number of times one can enter those lounges.

Related: Competitors pushed Delta to backtrack on its lounge and loyalty program changes

Some airlines saw the outcry with Delta as their chance to reassure customers that they would not raise their fees while others waited for the storm to pass to quietly implement their own increases.

A photograph captures a Qantas Airways lounge in Sydney, Australia.

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This is how much more you'll have to pay for Qantas lounge access

Australia's flagship carrier Qantas Airways  (QUBSF)  is the latest airline to announce that it would raise the cost accessing the 24 lounges across the country as well as the 600 international lounges available at airports across the world through partner airlines.

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Unlike other airlines which grant access primarily after reaching frequent flyer status, Qantas also sells it through a membership — starting from April 18, 2024, prices will rise from $600 Australian dollars ($392 USD)  to $699 AUD ($456 USD) for one year, $1,100 ($718 USD) to $1,299 ($848 USD) for two years and $2,000 AUD ($1,304) to lock in the rate for four years.

Those signing up for lounge access for the first time also currently pay a joining fee of $99 AUD ($65 USD) that will rise to $129 AUD ($85 USD).

The airline also allows customers to purchase their membership with Qantas Points they collect through frequent travel; the membership fees are also being raised by the equivalent amount in points in what adds up to as much as 17% — from 308,000 to 399,900 to lock in access for four years.

Airline says hikes will 'cover cost increases passed on from suppliers'

"This is the first time the Qantas Club membership fees have increased in seven years and will help cover cost increases passed on from a range of suppliers over that time," a Qantas spokesperson confirmed to Simple Flying. "This follows a reduction in the membership fees for several years during the pandemic."

The spokesperson said the gains from the increases will go both towards making up for inflation-related costs and keeping existing lounges looking modern by updating features like furniture and décor.

While the price increases also do not apply for those who earned lounge access through frequent flyer status or change what it takes to earn that status, Qantas is also introducing even steeper increases for those renewing a membership or adding additional features such as spouse and partner memberships.

In some cases, the cost of these features will nearly double from what members are paying now.

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PR55α-controlled PP2A Inhibits p16 Expression and Blocks Cellular Senescence Induction

“Our results show that PR55α specifically reduces p16 expression […]” Credit: 2024 Palanivel et al. “Our results show that PR55α specifically…

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“Our results show that PR55α specifically reduces p16 expression […]”

Credit: 2024 Palanivel et al.

“Our results show that PR55α specifically reduces p16 expression […]”

BUFFALO, NY- March 19, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 16, Issue 5, entitled, “PR55α-controlled protein phosphatase 2A inhibits p16 expression and blocks cellular senescence induction by γ-irradiation.”

Cellular senescence is a permanent cell cycle arrest that can be triggered by both internal and external genotoxic stressors, such as telomere dysfunction and DNA damage. The execution of senescence is mainly by two pathways, p16/RB and p53/p21, which lead to CDK4/6 inhibition and RB activation to block cell cycle progression. While the regulation of p53/p21 signaling in response to DNA damage and other insults is well-defined, the regulation of the p16/RB pathway in response to various stressors remains poorly understood. 

In this new study, researchers Chitra Palanivel, Lepakshe S. V. Madduri, Ashley L. Hein, Christopher B. Jenkins, Brendan T. Graff, Alison L. Camero, Sumin Zhou, Charles A. Enke, Michel M. Ouellette, and Ying Yan from the University of Nebraska Medical Center report a novel function of PR55α, a regulatory subunit of PP2A Ser/Thr phosphatase, as a potent inhibitor of p16 expression and senescence induction by ionizing radiation (IR), such as γ-rays. 

“During natural aging, there is a gradual accumulation of p16-expressing senescent cells in tissues [76]. To investigate the significance of PR55α in this up-regulation of p16, we compared levels of the p16 and PR55α proteins in a panel of normal tissue specimens derived from young (≤43 y/o) and old (≥68 y/o) donors.”

The results show that ectopic PR55α expression in normal pancreatic cells inhibits p16 transcription, increases RB phosphorylation, and blocks IR-induced senescence. Conversely, PR55α-knockdown by shRNA in pancreatic cancer cells elevates p16 transcription, reduces RB phosphorylation, and triggers senescence induction after IR. Furthermore, this PR55α function in the regulation of p16 and senescence is p53-independent because it was unaffected by the mutational status of p53. Moreover, PR55α only affects p16 expression but not p14 (ARF) expression, which is also transcribed from the same CDKN2A locus but from an alternative promoter. In normal human tissues, levels of p16 and PR55α proteins were inversely correlated and mutually exclusive. 

“Collectively, these results describe a novel function of PR55α/PP2A in blocking p16/RB signaling and IR-induced cellular senescence.”
 

Read the full paper: DOI: https://doi.org/10.18632/aging.205619 

Corresponding Authors: Michel M. Ouellette, Ying Yan

Corresponding Emails: mouellet@unmc.edu, yyan@unmc.edu

Keywords: p16, p14, CDKN2A locus, p53, RB, PR55α, PP2A, γ-irradiation

Click here to sign up for free Altmetric alerts about this article.

 

About Aging:

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Please visit our website at www.Aging-US.com​​ and connect with us:

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For media inquiries, please contact media@impactjournals.com.

 

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Wall Street Bonuses Fall For Second Year To 2019 Lows Amid Capital Markets Freeze

Wall Street Bonuses Fall For Second Year To 2019 Lows Amid Capital Markets Freeze

Wall Street bonuses have declined for two consecutive years,…

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Wall Street Bonuses Fall For Second Year To 2019 Lows Amid Capital Markets Freeze

Wall Street bonuses have declined for two consecutive years, falling to levels last seen in 2019, according to the latest yearly figures released by New York State Comptroller Thomas P. DiNapoli. This trend is occurring amidst a multi-year downturn in capital markets due to the Federal Reserve's interest rate hiking cycle.

According to the report, the average Wall Street cash bonus fell 2% to $176,500 in 2023, the lowest level since 2019. The drop was far less than the 25% plunge in 2022. Last year's bonus pool was $33.8 billion, unchanged from the previous year but far less than the $42.7 billion during the stock market mania in 2021. 

Source: Bloomberg 

"Wall Street's average cash bonuses dipped slightly from last year, with continued market volatility and more people joining the securities workforce," DiNapoli said in a news release on Tuesday. 

He continued: "While these bonuses affect income tax revenues for the state and city, both budgeted for larger declines so the impact on projected revenues should be limited." 

"The securities industry's continued strength should not overshadow the broader economic picture in New York, where we need all sectors to enjoy full recovery from the pandemic," he added.

Despite the slump, the report said Wall Street's profits rose 1.8% last year, "but firms have taken a more cautious approach to compensation, and more employees have joined the securities industry, which accounts for the slight decline in the average bonus." 

The report showed the industry employed 198,500 people in 2023, up from 191,600 the prior year. This expansion occurred during a period when US banks laid off 23,000 jobs. 

Given that swaps traders and economists at Goldman Sachs Group are forecasting fewer Fed interest-rate cuts this year, a higher-for-longer rates environment will continue to discourage capital-market activity. 

There's about a 50% chance of a June cut. Over the last several months, the Fed's interest-rate target implied by overnight index swaps and SOFR futures went from 700bps of cuts to currently 292bps of cuts for the full year. 

Any delay in the easing cycle will only mean another year of depressed bonuses for Wall Street. 

Tyler Durden Tue, 03/19/2024 - 10:00

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