Gene therapy gets a turbo boost

For decades, scientists have dreamt of a future where genetic diseases, such as the blood clotting disorder hemophilia, could be a thing of the past. Gene therapy, the idea of fixing faulty genes with healthy ones, has held immense promise. But a major hurdle has been finding a safe and efficient way to deliver those genes.

Now, researchers at the University of Hawai'i's John A. Burns School of Medicine (JABSOM) have made a significant breakthrough in gene editing technology that could revolutionize how we treat genetic diseases. Their new method offers a faster, safer, and more efficient way to deliver healthy genes into the body, potentially leading to treatments for hundreds of conditions. This research was recently published in Nucleic Acids Research.

Here's how it works.

Current methods can fix errors in genes, but they can also cause unintended damage by creating breaks in the DNA. Additionally, they struggle to insert large chunks of genetic material such as whole genes.

The new technique, developed by Dr. Jesse Owens along with his team Dr. Brian Hew, Dr. Ryuei Sato and Sabranth Gupta, from JABSOM's Institute for Biogenesis Research and Cell and Molecular Biology Department, addresses these limitations. They used laboratory evolution to generate a new super-active integrase capable of inserting therapeutic genes into the genome at record-breaking efficiencies.

"It's like having a "paste" function for the human genome," said Dr. Owens. "It uses specially engineered 'integrases' to carefully insert healthy genes into the exact location needed, without causing breaks in the DNA. This method is much more efficient, with success rates of up to 96% in some cases."

"This could lead to faster and more affordable treatments for a wide range of diseases, potentially impacting hundreds of conditions with a single faulty gene," said Dr. Owens.

Faster Development of Treatments and a Broader Range of Applications

The implications of this research extend beyond gene therapy. The ability to efficiently insert large pieces of DNA has applications in other areas of medicine.

When making cell lines to produce therapeutic proteins, the gene encoding the protein is usually randomly inserted into the genome, and it rarely lands in a location in the genome that is good for production. This is like searching for a needle in a haystack. Additionally, finding a cell with the gene inserted correctly and producing the desired protein can take many months.

Instead of searching for a needle in a haystack, Dr. Owens' technique makes a stack of needles. It delivers the gene directly to the desired location, significantly speeding up the development process.

"JABSOM takes pride in nurturing talented researchers like Jesse Owens, whose work has the power to create a global impact," said Sam Shomaker, dean of the University of Hawai'i John A. Burns School of Medicine. "This research, conducted in our lab in the middle of the Pacific, has the potential to significantly improve the way we treat genetic diseases."

Dr. Owens' team is exploring how this technique could accelerate the development and manufacture of biologics and advanced therapies such as antibodies. Currently, finding the right cell line for efficient production can be a time-consuming process. However, Dr. Owens' new genome engineering tool can reduce the cell line development timeline and accelerate the manufacture of life-saving therapeutics.

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Metabolism, not genes, may offer more insight into risk of some diseases

Our ancestry can be detected not only in our genes, but also in our metabolism, a new Yale-led study has found.

In an analysis of the metabolic profiles of healthy American babies, researchers found surprising differences among ethnic groups which may help make screening for inherited metabolic disorders, cystic fibrosis, or hypothyroidism much more accurate than traditional genetic disease screens.

"We don't want to miss a baby who is potentially sick, and we don't want to put families through the burdens and concerns that can stem from a false-positive test," said Curt Scharfe, associate professor of genetics at Yale School of Medicine and senior author of the study published in the journal Molecular Genetics and Metabolism.

For the study, Scharfe and colleagues analyzed data collected from more than 400,000 babies, representing 17 self-reported ethnic groups, who were part of California's newborn screening program. Specifically, they wanted to know if these ethnic differences could be detected in metabolites, molecules that provide energy by breaking down food or body tissue such as fat, found in the blood of the infants.

The question was not only of academic interest but of concern to pediatricians. For instance, it is known that babies of African heritage are more likely to have elevated blood biomarkers indicating cystic fibrosis than babies born to white parents, even though babies born to white parents are far more likely to eventually develop the disease. Researchers hope that using ancestry to interpret these differences in marker levels might offer more accurate ways to assess risks than traditional genetic tests.

People of African heritage are also known to have greater genetic diversity than those from ethnic groups because they are descendants of the world's oldest ancestral population. Modern humans emigrated from Africa to regions across the planet; other ethnic groups are descendants of these original migrants, and have enough variation in their DNA to make them genetically identifiable.

But metabolic lineages can tell a different story, the researchers found. For instance, while there is a clear delineation between genetic variants among African-Americans and Americans of European descent, researchers found that metabolically these two groups are more closely related. Conversely, while people of Japanese and Chinese descent, for instance, are closely related genetically, the researchers found larger differences in their metabolic profiles.

"This attests to the role of environment in forming our metabolism," Scharfe said. "Where people share the same culture and food, metabolic profiles are more similar. Where people are separated by circumstances, such as language or lifestyles, then differences in metabolism are greater than genetic variations."

Scharfe cautions that more work needs to be done before findings can be applied clinically. Researchers only analyzed 41 out of many hundreds of metabolites and relied on parents own reports of their ethnic heritage, which might not always correspond to reality.

"This is just a first snap shot, but understanding our metabolic ancestry has a promising future," Scharfe said.

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Single test for over 50 genetic diseases will cut diagnosis from decades to days

A new DNA test, developed by researchers at the Garvan Institute of Medical Research in Sydney and collaborators from Australia, UK and Israel, has been shown to identify a range of hard-to-diagnose neurological and neuromuscular genetic diseases quicker and more-accurately than existing tests.

'We correctly diagnosed all patients with conditions that were already known, including Huntington's disease, fragile X syndrome, hereditary cerebellar ataxias, myotonic dystrophies, myoclonic epilepsies, motor neuron disease and more,' says Dr Ira Deveson, Head of Genomics Technologies at the Garvan Institute and senior author of the study.

The diseases covered by the test belong to a class of over 50 diseases caused by unusually-long repetitive DNA sequences in a person's genes -- known as 'Short Tandem Repeat (STR) expansion disorders'.

'They are often difficult to diagnose due to the complex symptoms that patients present with, the challenging nature of these repetitive sequences, and limitations of existing genetic testing methods,' says Dr Deveson.

The study, published today in Science Advances, shows that the test is accurate, and allows the team to begin validations to make the test available in pathology services around the world.

A patient who participated in the study, John, first realised something wrong when he experienced unusual problems balancing during a ski lesson.

'It was very worrying having symptoms that, over the years, increased in severity; from being active and mobile to not being able to walk without support. I had test after test for over ten years and absolutely no answers as to what was wrong,' says John, who was eventually diagnosed with a rare genetic disease called CANVAS, which affects the brain.

'It was reassuring to finally confirm my diagnosis genetically, and it's exciting to know that, in the near future, others with these types of conditions will be able to get a diagnosis quicker than I did,' he says.

'For patients like John, the new test will be a game-changer, helping to end what can often be a taxing diagnostic odyssey,' says Dr Kishore Kumar, a co-author of the study and clinical neurologist at the Concord Hospital.

Repeat expansion disorders can be passed on through families, can be life threatening and generally involve muscle and nerve damage, as well as other complications throughout the body.

Quicker, more-accurate diagnosis for patients avoids 'diagnostic odyssey'

Current genetic testing for expansion disorders can be 'hit and miss', says Dr Kumar. 'When patients present with symptoms, it can be difficult to tell which of these 50-plus genetic expansions they might have, so their doctor must decide which genes to test for based on the person's symptoms and family history. If that test comes back negative, the patient is left without answers. This testing can go on for years without finding the genes implicated in their disease. We call this the 'diagnostic odyssey', and it can be quite stressful for patients and their families,' he says.

'This new test will completely revolutionise how we diagnose these diseases, since we can now test for all the disorders at once with a single DNA test and give a clear genetic diagnosis, helping patients avoid years of unnecessary muscle or nerve biopsies for diseases they don't have, or risky treatments that suppress their immune system,' says Dr Kumar.

Although repeat expansion disorders cannot be cured, a quicker diagnosis can help doctors identify and treat disease complications earlier, such as heart issues associated with Friedreich's ataxia.

Scanning for known and novel diseases

Using a single DNA sample, usually extracted from blood, the test works by scanning a patient's genome using a technology called Nanopore sequencing.

'We've programmed the Nanopore device to hone in on the roughly 40 genes known to be involved in these disorders and to read through the long, repeated DNA sequences that cause disease,' he says. 'By unravelling the two strands of DNA and reading the repeated letter sequences (combinations of A, T, G or C), we can scan for abnormally long repeats within the patient's genes, which are the hallmarks of disease.'

'In the one test, we can search for every known disease-causing repeat expansion sequence, and potentially discover novel sequences likely to be involved in diseases that have not yet been described,' says Dr Deveson.

Upscaling to wider use in the next five years

The Nanopore technology used in the test is smaller and cheaper than standard tests, which the team hopes will smooth its uptake into pathology labs. 'With Nanopore, the gene sequencing device has been reduced from the size of a fridge to the size of a stapler, and costs around $1000, compared with hundreds of thousands needed for mainstream DNA sequencing technologies' says Dr Deveson.

The team expects to see their new technology used in diagnostic practice within the next two to five years. One of the key steps towards that goal is to gain appropriate clinical accreditation for the method.

Once accredited, the test will also transform research into genetic diseases, says Dr Gina Ravenscroft, a co-author of the study and a researcher working on rare disease genetics at the Harry Perkins Institute of Medical Research.

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