Postdoctoral fellow Samagya Banskota (left) and graduate student Aditya Raguram, co-lead authors of the study, investigate in vivo delivery of therapeutic proteins at the Liu Lab.
Photo by Julia McCreary
Researchers able to edit genes linked to high cholesterol and partially restore vision in mice
A team of researchers led by Harvard and Broad Institute scientists has developed a new drug-delivery system using engineered DNA-free virus-like particles (eVLPs) that is able to edit genes associated with high cholesterol and partially restore vision in mice.
Because eVLPs enable safer in vivo delivery of gene-editing agents than some clinical methods with comparable or higher efficiencies, this new platform holds promise of being able to deliver therapeutic macromolecules with less risk of off-target editing or DNA integration.
In the paper, published in Cell, the researchers detail how they developed virus-like particles to deliver base editors, proteins that make programmable single-letter changes in DNA, and CRISPR-Cas9 nuclease, a protein that cuts DNA at targeted sites in the genome. The authors identified factors that influence virus-like-particle delivery efficiency and demonstrated that engineering these particles can overcome multiple structural limits to their potency. The team’s eVLPs are the first virus-like particles to deliver therapeutic levels of base editors to a variety of cell types in adult animals.
“The delivery of therapeutic macromolecules into mammalian cells in animals, and eventually in patients, is one of the most important challenges in life sciences,” said the paper’s senior author, David Liu, the Thomas Dudley Cabot Professor of the Natural Sciences and a core faculty member of the Broad. “There is often a very steep drop-off between in vitro and in vivo delivery, so we made the decision early on that our new delivery technology would need to show good efficacy in animal models.”
This work was led by members of Liu’s lab, including postdoctoral fellow Samagya Banskota, and Aditya Raguram, a chemical biology student in the Graduate School of Arts and Sciences, in collaboration with research teams led by Krzysztof Palczewski at UC Irvine, and Kiran Musunuru at the University of Pennsylvania.
This new delivery system finds a novel use for virus-like particles and builds on the success of base editors, which the Liu Lab developed in 2016, to rewrite individual DNA bases such as the mutations that cause thousands of genetic diseases.
Virus-like particles have long been studied as drug-delivery vehicles. Because they can carry molecular cargo and lack viral genetic material, they are able to exploit the efficiency and tissue-targeting advantages of viral delivery without the drawbacks of using actual viruses, which can insert their genetic material into a cell’s genome and potentially cause cancer and other diseases. However, existing VLP-delivery strategies have had limited therapeutic efficacy in vivo.
The team identified delivery limitations and systematically engineered the components of VLPs to overcome cargo packaging, release, and localization bottlenecks. In doing so, they developed fourth-generation eVLPs that packaged 16 times more cargo proteins than previous designs and enabled an eight- to 26-fold increase in editing efficiency in cells and animals.
The team tested their optimized eVLP system to deliver base editors to the liver in mice, where they efficiently edited a gene that can lower “bad” cholesterol levels. A single injection of eVLPs resulted in an average of 63 percent editing of the target gene and a 78 percent drop in its protein levels, which substantially reduce the risk of coronary heart disease.
“The cholesterol target is particularly interesting because it is not only relevant to patients with a rare genetic disease,” Raguram said. “We are hopeful this is one example of genome editing being able to benefit a large population because cholesterol levels impact the health of billions of people.”
The researchers also used a single eVLP injection to correct a disease-causing mutation in mice with a genetic retinal disorder, resulting in the partial restoration of vision.
Going forward, Banskota is optimistic that eVLPs will be utilized by scientists quite easily because of the system’s relative simplicity and versatility.
“Because our system is relatively simple and easily engineered, it allows other scientists to adopt and build upon this technology quickly,” Banskota said. “Beyond carrying gene editors, eVLPs have the ability to transport other macromolecules with lots of therapeutic potential.”
Original Article: Drug delivery system offers hope for treating genetic diseases
More from: Harvard University | Broad Institute | University of Pennsylvania
The Latest Updates from Bing News & Google News
Go deeper with Bing News on:
Engineered DNA-free virus-like particles
- Engineered living materials: Scientists 3D print with bio-ink made from tobacco cells
Using a 3D printer and a bioink, scientists create an "engineered plant living material" (EPLM) that harnesses the power of cells.
- HIV and AIDS News
Breakthrough in Developing the PD-1-Enhanced DNA Vaccine for Over 6-Year cART-Free AIDS Prevention and ... 2024 — A new study shows virus-like particle can effectively 'shock and kill' latent ...
- Virtual Viruses Reveal Complex Genomic Dynamics
A virus may be microscopic, but it contains thousands of nucleic acid bases strategically packaged into a protein shell. Knowing how the virus organizes these vast information stores in a compact ...
- Cloaking Device: Liu, Joung Launch $100M Nvelop Therapeutics to Advance Delivery of Genetic Cargo
One of Nvelop’s approaches, originating from Liu’s lab, centers on engineered DNA-free virus-like particles (eVLPs)—assemblies of viral proteins that can infect cells but lack viral genetic ...
- Exploring why viruses cause lesions and rashes
The virus is just 1 of many orthopoxviruses—some, like smallpox and mpox ... coarse-textured lesions. Viral particles can then be released from the wart to infect other body sites or hosts.
Go deeper with Google Headlines on:
Engineered DNA-free virus-like particles
[google_news title=”” keyword=”engineered DNA-free virus-like particles” num_posts=”5″ blurb_length=”0″ show_thumb=”left”]
Go deeper with Bing News on:
eVLPs
- Vaccines Market Worth $94.9 billion | MarketsandMarkets
Vaccines Market in terms of revenue was estimated to be worth $78.0 billion in 2024 and is poised to reach $94.9 billion by 2029, growing at a CAGR of ...
- Vaccines Market Worth $94.9 billion | MarketsandMarkets™
CHICAGO, April 24, 2024 /PRNewswire/ -- Vaccines Market in terms of revenue was estimated to be worth $78.0 billion in 2024 and is poised to reach $94.9 billion by 2029, growing at a CAGR of 4.0% ...
- Former bluebird execs hope to fly new startup to 'cutting edge' of gene therapy delivery tech
Both utilize engineered viruslike particles (eVLPs), which are loaded up with gene editing machinery and sent to specific cells. Ideally, eVLPs overcome the safety issues with virus-based ...
- Cloaking Device: Liu, Joung Launch $100M Nvelop Therapeutics to Advance Delivery of Genetic Cargo
One of Nvelop’s approaches, originating from Liu’s lab, centers on engineered DNA-free virus-like particles (eVLPs)—assemblies of viral proteins that can infect cells but lack viral genetic ...
- Canada funds VBI Vaccines' novel vaccine technology development
The MLE technology integrates a structural viral protein core into the mRNA vaccine, instructing cells to produce not only target antigens but also enveloped virus-like particles (eVLPs) that ...
Go deeper with Google Headlines on:
eVLPs
[google_news title=”” keyword=”eVLPs ” num_posts=”5″ blurb_length=”0″ show_thumb=”left”]