Round up: Synthetic DNA nanoparticles for gene therapy, new model to find treatments for an aggressive blood cancer, and more

Health Tech World explores the latest developments in the world of health technology.

Synthetic DNA nanoparticles for gene therapy

A grant has been awarded for research in synthetic DNA nanoparticles, which have potential applications in gene therapy.

The grant will support work in synthesising nanoparticles and studying how they behave inside cells in a laboratory using single-cell injections and a microscope to track the nanoparticles and watch what happens to them over time inside individual cells.

DNA nanoparticles are highly programmable and could be designed to encode a gene that replaces a missing or malfunctioning gene, instructing a cell to produce a needed protein or correct a genetic error.

“In many genetic diseases, scientists know the gene that needs to be corrected,” said Case Western Reserve University chemist Divita Mathur who was awarded the National Science Foundation (NSF) Faculty Early Career Development Program (CAREER) grant for her research.

“The problem is the delivery. It’s easy to deliver things to the liver, so liver-based therapies are in clinical trials. Converting this to another area of the body is difficult, which is one of the things that motivates us to pursue this research.”

Mathur said that eventually these DNA nanoparticles could also be designed with an attachment that functions like a barcode on an envelope, sending it to a particular address, or in this case, targeting a particular kind of cell.

“We want to show students how molecules are three-dimensional, how they occupy space and how they have a specific orientation in space, like right or left-handedness,” she said.

Molecule developed that illuminates nerve tissue, helping make surgery faster and safer

When surgeons dissect tissue to remove a tumour or make a repair they must work cautiously, relying on electrophysical monitors and their own anatomical knowledge to avoid cutting nerves, which could complicate the patient’s recovery.

Now, a surgeon has helped develop and test a first-of-its-kind drug that binds to nerve tissue and fluoresces – emits light – enabling surgeons to better see the nerves they’re trying to work around.

Researchers have reported that bevonescein, a short chain of amino acids attached to a fluorescing molecule, was safe to use highlighted longer stretches of nerves than would be visible to the naked eye, improving the odds of operating without causing injury.

A larger Phase 3 study currently underway includes patients at UNM Hospital and is expected to be completed by this summer that will assess whether use of the imaging agent meaningfully improves overall surgical outcomes, something the initial trial was not designed to determine.

Patients in the trials receive an IV infusion of the drug prior to surgery, but it is quickly cleared by the kidneys. In the operating room, surgeons use microscopes with special lights and filters that illuminate the surgical site at a specific frequency that causes the drug to fluoresce.

The nerves appear as wormlike yellowish-green structures that thread through the surrounding tissue.

An upcoming phase of the research will evaluate the use of specially modified headband-mounted magnifying loops of the sort that surgeons wear, rather than the microscope.

If the Phase 3 trial shows clear clinical benefit from the use of bevonescein during head and neck surgery it could win FDA approval, leading to wider use in surgical procedure throughout the body.

AI sharpens pathologists’ interpretation of tissue samples

Pathologists’ have improved their examinations of tissue samples from skin cancer tumours by using an AI tool.

According to the team, the assessments became more consistent and patients’ prognoses were described more accurately when using the tool.

It is already known that tumour-infiltrating lymphocytes (TILs) are an important biomarker in several cancers, including malignant melanoma (skin cancer). TILs are immune cells found in or near the tumour, where they influence the body’s response to the cancer.

In malignant melanoma, the presence of TILs plays a role in both diagnosis and prognosis, with a high presence being favourable. An important part of pathologists’ work in malignant melanoma is to estimate the amount of TILs.

The researchers at Karolinska Institutet investigated how pathological assessments were affected by an AI tool trained to quantify TILs.

The study included 98 pathologists and researchers from other professions divided into two groups. One group consisted solely of experienced pathologists. They worked ‘as usual’, i.e. they looked at digital images of stained tissue sections and estimated the amount of TILs according to current guidelines. The second group included pathologists, but also researchers from other professions – all of whom had some experience in assessing pathological images. They also looked at the images ‘as usual,’ but were assisted by AI support that quantified the amount of TILs.

Everyone assessed 60 tissue sections, all from patients with malignant melanoma. The study was retrospective, so the images showed tissue samples from patients whose diagnosis and treatment had already been determined.

The assessments made with AI support were superior to the others in several ways. Among other things, reproducibility was very high, and the results were very similar regardless of who performed the review.

This is important because assessments of TILs can currently vary depending on who performs them, which can compromise medical safety. The AI-supported assessments also provided a more accurate picture of the patients’ disease prognoses, and, since the study was retrospective, there was a ‘correct answer’ to compare with. However, this outcome was unknown to those who assessed the images.

New model to find treatments for an aggressive blood cancer

Researchers working on an incurable blood cancer can now use a new lab model which could make testing potential new treatments and diagnostics easier and quicker, new research has found.

A team of researchers have studied blood cells from patients with a blood cancer called myelodysplastic syndrome disease (MDS). This disease often develops into a highly aggressive form of Acute Myeloid Leukaemia (AML).

Working with this new model has led to confirmation that a mutation in the gene CEBPA causes progression from MDS to AML.

The team set out to examine whether changes to the gene CEBPA were driving disease progression in patients with MDS, or whether mutations were a passenger as the blood cancer developed into the more serious AML.

Taking blood cells from a patient that was diagnosed with MDS, the team reprogrammed these cells into iPSCs using a genetic trick. Once obtained, these cells can give rise to any cell type of the body.

They then used sophisticated cell culture methods to convert them into white blood cells and red blood cells in the lab. Using multiple tests, they showed that the lab-grown cells behaved just like the patient’s real cells.

Using patient cells that were obtained early during disease progression without the mutation, the researchers were then able to modify the cells’ genome to include the mutation in CEBPA gene as it happened in the patient two years after being diagnosed with MDS.

This change made the disease more aggressive: it reduced the number of healthy cells, blocked the formation of white blood cells, and aberrant cells were formed that divide more rapidly, even when they were treated with chemotherapy, mimicking what happened to the patient.

The research group has said it is open to collaboration, licensing, or partnering opportunities.

New molecular tool sheds light on how cancer cells repair telomeres

Each time a cell divides, a small section of each chromosome’s protective cap, the telomere, is worn away. Most cells use an enzyme called telomerase to help mitigate this loss, but 10 per cent to 15 per cent of cancers have another mechanism called the alternative lengthening of telomeres (ALT) pathway.

In a new study, published in Molecular Cell, researchers describe a novel tool called BLOCK-ID that offers a glimpse into the black box of ALT, bringing them one step closer to developing cancer therapies that target this process.

During cell division, the double helix of DNA unwinds to create a replication fork, allowing replication proteins access to do their job. But sometimes, this process stalls and the proteins become stuck on DNA, creating what is known as a protein barrier.

The researchers say that BLOCK-ID is like an artificial barrier that allows the monitoring of a collision event at one very specific part of the cell. It uses an enzyme to add a molecule called biotin to all proteins that play a role at the collision event.

“Biotin acts like a tag that says, ‘This protein has been in contact with the protein barrier,’” said Roderick O’Sullivan, professor in the Department of Pharmacology and Chemical Biology at the University of Pittsburgh and UPMC Hillman Cancer Center.

“Even though proteins may move to another part of the cell, we can tell they were at the collision event because they are marked for life, allowing us to trace brief interactions that would normally be missed.”

Using BLOCK-ID, the researchers identified a protein called TRIM24 as an essential player in the ALT pathway of cancer cells.

“If you remove TRIM24 from normal cells, they can tolerate it, but if you remove this protein from ALT cells, they don’t like it,” said O’Sullivan.

“Without TRIM24, telomeres in ALT cells become a mess: they shorten, and they become destabilised and non-functional.”

Until now, it had been thought that a protein called PML was essential for ALT because it forms a shell around telomeres, creating a specialized environment that attracts other repair proteins. However, when the researchers molecularly tethered TRIM24 to telomeres in cancer cells lacking PML, they found that, surprisingly, these telomere repair shells still formed.

“This experiment tells us how important TRIM24 is to the ALT mechanism,” said O’Sullivan. “It also tells us that ALT has inbuilt redundancies. This is really important because if we are going to target ALT, we need to understand its complexities.”