Nav: Home

Plant-based relatives of cholesterol could give boost to gene therapy

February 20, 2020

PORTLAND, Ore. - Gene-infused nanoparticles used for combating disease work better when they include plant-based relatives of cholesterol because their shape and structure help the genes get where they need to be inside cells.

The findings by Oregon State University researchers, published today in Nature Communications, are important because many illnesses that can't be treated effectively with conventional drugs can be treated genetically - delivering nucleic acids to diseased cells so they can make the correct proteins needed for health.

Those genetic treatments rely on the transport devices reaching their destination with a high success rate and releasing their cargo effectively.

Gaurav Sahay, assistant professor of pharmaceutical sciences in the OSU College of Pharmacy, studies lipid-based nanoparticles as a gene delivery vehicle, with a focus on cystic fibrosis.

Cystic fibrosis is a progressive genetic disorder that results in persistent lung infection and afflicts 30,000 people in the U.S., with about 1,000 new cases diagnosed every year.

More than three-quarters of patients are diagnosed by age 2, and despite steady advances in alleviating complications, the median life expectancy of cystic fibrosis patients is still just 40 years.

One faulty gene - the cystic fibrosis transmembrane conductance regulator, or CFTR - causes the disease, which is characterized by lung dehydration and mucous buildup that blocks the airway.

Two years ago, Sahay and other scientists and clinicians at OSU and Oregon Health & Science University demonstrated proof-of-concept for a new, improved cystic fibrosis therapy: loading chemically modified CFTR messenger RNA into lipid-based nanoparticles, creating molecular medicine that could simply be inhaled at home.

The mRNA-loaded nanoparticle approach causes cells to make the correct protein, allowing cells to properly regulate chloride and water transport, which is critical to healthy respiratory function.

Cholesterol, a waxy substance the body uses to make healthy cells, is thought to provide stability in these gene nanocarriers. In the latest study, Sahay and collaborators boosted gene delivery by using plant-based analogs of cholesterol instead. Another plus of these plant-derived sterols is a cardiovascular health benefit, he adds.

The type of nanoparticle used to deliver genes in this study has already been clinically approved; it's being used in a drug, trade-named Onpattro, given to patients with a progressive genetic condition called amyloidosis, which disrupts organ function through harmful deposits of the amyloid protein.

Sahay and graduate student Siddharth Patel, first author on the study, found that phytosterols - plant-based molecules chemically similar to cholesterol - change the shape of the nanoparticles from spherical to polyhedral and cause them move faster.

That's important because once inside a cell, the nanoparticles need maneuverability for the escape they need to make: from a cell compartment known as an endosome into the cytosol, where the delivered genes can perform their intended function.

"One of the biggest challenges in the delivery of genes is that less than 2% of the nanoparticles reach the cytosol," said Sahay, who also holds an adjunct faculty position with OHSU. "If you up the dose to get more genes there, now you have problems with toxicity, plus the cost goes higher. But the nanoparticles' shape changes because of these naturally occurring cholesterol analogs, and the new shape helps them deliver genes better. The analogs boost gene delivery 10-fold and sometimes 200-fold."

The finding can be used to make inhalable particles that can cross several barriers in the lung in a cystic fibrosis patient, enabling patients to be treated with much higher efficacy, Sahay added.

"In this latest research, we hypothesized that with the analog inclusions, there would be shape changes and changes with how the nanoparticles interact with the cell and how the cell perceives them," Patel said. "For instance, the sterols might help them get to the ribosomes for translation faster. This opens up a whole new area of research - the shape and structure and composition of the liquid nanoparticles now become quite relevant. We're just scratching the surface on the way to building LNPs with a rational design to get different properties for treating different diseases with cell-type specificity."
Scientists at Duke University and Moderna Therapeutics, a Massachusetts-based biotech firm that is a leader in mRNA-based gene therapy, also collaborated on the study.

The National Heart, Lung and Blood Institute, the National Institute of Biomedical Imaging and Bioengineering, the Cystic Fibrosis Foundation, Moderna Therapeutics and the College of Pharmacy supported the research.

The Cystic Fibrosis Foundation has awarded Sahay an additional $800,000 to continue this work, pushing him past the $4.5 million mark in funding from all sources to study cystic fibrosis therapies.

Oregon State University

Related Nanoparticles Articles:

How to get more cancer-fighting nanoparticles to where they are needed
University of Toronto Engineering researchers have discovered a dose threshold that greatly increases the delivery of cancer-fighting drugs into a tumour.
Nanoparticles: Acidic alert
Researchers of Ludwig-Maximilians-Universitaet (LMU) in Munich have synthesized nanoparticles that can be induced by a change in pH to release a deadly dose of ionized iron within cells.
3D reconstructions of individual nanoparticles
Want to find out how to design and build materials atom by atom?
Directing nanoparticles straight to tumors
Modern anticancer therapies aim to attack tumor cells while sparing healthy tissue.
Sweet nanoparticles trick kidney
Researchers engineer tiny particles with sugar molecules to prevent side effect in cancer therapy.
A megalibrary of nanoparticles
Using straightforward chemistry and a mix-and-match, modular strategy, researchers have developed a simple approach that could produce over 65,000 different types of complex nanoparticles.
Dialing up the heat on nanoparticles
Rapid progress in the field of metallic nanotechnology is sparking a science revolution that is likely to impact all areas of society, according to professor of physics Ventsislav Valev and his team at the University of Bath in the UK.
Illuminating the world of nanoparticles
Scientists at the Okinawa Institute of Science and Technology Graduate University (OIST) have developed a light-based device that can act as a biosensor, detecting biological substances in materials; for example, harmful pathogens in food samples.
What happens to gold nanoparticles in cells?
Gold nanoparticles, which are supposed to be stable in biological environments, can be degraded inside cells.
Lighting up cardiovascular problems using nanoparticles
A new nanoparticle innovation that detects unstable calcifications that can trigger heart attacks and strokes may allow doctors to pinpoint when plaque on the walls of blood vessels becomes dangerous.
More Nanoparticles News and Nanoparticles Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at     You can read The Transition Integrity Project's report here.