A Scottish patient has become the first person in the world to receive a pioneering therapy aimed at improving outcomes for those having heart bypass surgery. The treatment involves precisely editing DNA in veins to be used during heart bypass surgery to boost the production of a protective protein.
The treatment could help extend the lifespan of blood vessels used during the surgery and significantly improve patient health, experts say.
Cause of failures in bypass surgery
Heart bypass surgery – an operation to improve blood flow to the heart – is a life-saving treatment for patients with coronary heart disease.
The process typically uses one artery and two or more veins as bypass grafts – healthy blood vessels used to bypass a narrowed or blocked artery – creating a new route for blood to flow.
Vein grafts used in this type of surgery can fail because they are not naturally designed to withstand the high pressure of blood flow from the heart.
Protecting vein grafts
The PROTECT study, led by NHS Greater Glasgow and Clyde and the University of Glasgow in collaboration with NHS Golden Jubilee and the University of Edinburgh, is trialling a new gene therapy designed to support newly grafted blood vessels.
The treatment will introduce a gene, which produces a protein called TIMP-3, into the vein to be grafted.
TIMP-3 is involved in tissue remodelling. Higher levels of the protein could help to prevent thickening and blockage of the blood vessel over time, scientists say.
Exciting milestone
The research team has developed a way to treat the graft directly at the time of surgery, safely and efficiently delivering the gene therapy to the affected tissue before grafting into the heart.
It is hoped the treatment will help to extend a patient’s healthy life expectancy and reduce the need for further surgeries, experts say.
Imagine knowing in your 20s or 30s that you carry a gene which will cause your mind and body to slowly unravel. Huntington’s disease is inherited, relentless and fatal, and there is no cure. Families live with the certainty of decline stretching across generations.
Now, a new treatment is being widely reported as a breakthrough.
Last week, gene therapy company uniQure announced that a one-time brain infusion appeared to slow the disease in a small clinical study.
If confirmed, this would not only be a landmark for Huntington’s disease but potentially the first time a gene therapy has shown promise in any adult-onset neurodegenerative disorder.
But the results, which were announced in a press release, are early, unreviewed and based on external comparisons. So, while these findings offer families hope after decades of failure, we need to remain cautious.
Symptoms usually start in mid-life. They include involuntary movements, depression, irritability and progressive decline in thinking and memory. People lose the ability to work, manage money, live independently and eventually care for themselves. Most die ten to 20 years after onset.
The disease is caused by an expanded stretch of certain DNA repeats (CAG) in the huntingtin gene. The number of repeats strongly influences when symptoms begin, with longer expansions usually linked to earlier onset.
Looking for a treatment
The gene that causes Huntington’s disease was identified in 1993, 32 years ago. Soon afterwards, mouse studies showed that switching off the mutant huntingtin protein even after symptoms had begun could reverse signs and improve behaviour.
This suggested lowering the toxic protein might slow or even partly reverse the disease. Yet for three decades, every attempt to develop a therapy for people has failed to show convincing clinical benefit. Trials of huntingtin-lowering drugs and other approaches did not slow progression.
What is the new treatment?
The one-time gene therapy, called AMT-130, involves brain surgery guided by MRI. Surgeons infuse an engineered virus directly into the caudate and putamen brain regions, which are heavily affected in Huntington’s.
The virus carries a short genetic “microRNA” designed to reduce production of the affected huntingtin protein.
By delivering it straight into the brain, the treatment bypasses the blood–brain barrier. This natural wall usually prevents medicines from entering the central nervous system. That barrier helps explain why so many brain-targeted drugs have failed.
What did they find?
Some 29 patients received treatment, with 12 in each group (one low-dose, and one high-dose) followed for three years. According to uniQure, those given the higher dose declined much slower than expected.
The study compared how much participants’ movement, thinking and daily function declined, compared to a matched external group from a global Huntington’s registry (meaning they weren’t part of the study). The company claimed those given the higher dose had a 75% slowing in their decline.
On a functional scale focused on independence, the company reported a 60% slowing in decline for the higher dose group.
Other tests of movement and thinking also favoured treatment. Nerve-cell damage in spinal fluid was lower for study participants than would be expected for untreated patients.
Why should we be cautious?
These findings are an early snapshot of results reported by the company, not yet peer-reviewed. The study compared treated patients to an external matched control group, not people randomised to placebo at the same time. This design can introduce bias. The numbers are also small – only 12 patients at the three-year mark – so we can’t draw solid conclusions.
The company reports the therapy was generally well tolerated, with no new serious adverse events related to the drug since late 2022. Most problems were related to the neurosurgical infusion itself, and resolved. But in a disease that already causes such severe symptoms, it is often hard to know what counts as a side effect.
The company uniQure has said it plans to seek regulatory approval in 2026 on the basis of this dataset.
Regulators will face difficult decisions: whether to allow access sooner before all the questions and uncertainties are addressed – based on the needs of a community with no effective options – and wait for further data while people are being treated, or to insist on larger trials that confirm results before approval.
What does it mean?
If upheld, these results represent the first convincing signs that a gene-targeted therapy can slow Huntington’s disease. They may also be the first evidence of benefit from a gene therapy in any adult-onset neurodegenerative disorder. That would be a milestone after decades of failure.
But these results do not prove success. Only larger, longer and fully peer-reviewed studies will show whether this treatment truly changes lives. Even if approved, a complex neurosurgical gene therapy may not be easily accessible to all patients.
The company has said the drug’s price would be similar to other gene therapies – which can cost over A$3 million per patient – and will have the added cost of brain surgery.
The takeaway
For families who carry this gene, the hope is profound. But caution is just as important.
We may be witnessing the first credible step toward slowing an inherited adult-onset neurodegenerative disease, or just an early signal that may not hold up.
Ultimately, only time and rigorous science will show whether this treatment delivers the benefits so urgently needed.
CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way.
Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH
Since its breakthrough development more than a decade ago, CRISPR has revolutionised DNA editing across a broad range of fields, including new therapies for an array of disorders spanning cancers, blood conditions and diabetes. But in some cases, the DNA repair process leaves in unintentional, harmful edits. Now, University of California San Diego researchers have developed a new system to understand these repair outcomes and where they can go wrong. The system is described in Nature Communications.
In some designed treatments, patients are injected with CRISPR-treated cells or with packaged CRISPR components with a goal of repairing diseased cells with precision gene edits. Yet, while CRISPR has shown immense promise as a next-generation therapeutic tool, the technology’s edits are still imperfect. CRISPR-based gene therapies can cause unintended but harmful “bystander” edits to parts of the genome, at times leading to new cancers or other diseases.
Unravelling the complex biological dynamics behind both on- and off-target CRISPR edits is daunting, since intricate bodily tissues feature thousands of different cell types and CRISPR edits can depend on many different biological pathways.
Postdoctoral Scholar Zhiqian Li, Professor Ethan Bier and their colleagues developed a sequence analyser to help track on- and off-target mutational edits and the ways they are inherited from one generation to the next. Based on a concept proposed by former UC San Diego researcher David Kosman, the Integrated Classifier Pipeline (ICP) tool can reveal specific categories of mutations resulting from CRISPR editing.
Developed in flies and mosquitoes, the ICP provides a “fingerprint” of how genetic material is being inherited, which allows scientists to follow the source of mutational edits and related risks emerging from potentially problematic edits.
“The ICP system can cleanly establish whether a given individual insect has inherited specific genetic components of the CRISPR machinery from either their mothers or fathers since maternal versus paternal transmission result in totally different fingerprints,” said Bier, a professor in the UC San Diego School of Biological Sciences.
The ICP can help untangle complex biological issues that arise in determining the mechanisms behind CRISPR. While developed in insects, ICP carries vast potential for human applications.
“There are many parallel applications of ICP for analysing and following CRISPR editing outcomes in humans following gene therapy or during tumour progression,” said study first author Li. “This transformative flexible analysis platform has many possible impactful uses to ensure safe application of cutting-edge next-generation health technologies.”
ICP also offers help in tracking inheritance across generations in gene drive systems, which are new technologies designed to spread CRISPR edits in applications such as stopping the transmission of malaria and protecting agricultural crops against pest destruction. For example, researchers could select a single mosquito from the field where a gene-drive test is being conducted and use ICP analysis to determine whether that individual had inherited the genetic construct from its mother or its father, and whether it had inherited a defective element lacking the defining visible markers of that genetic element.
“The CRISPR editing system can be more than 90 percent accurate,” said Bier, “but since it edits over and over again it will eventually make a mistake. The bottom line is that the ICP system can give you a very high-resolution picture of what can go wrong.”
A group of patients with a hereditary angioedema disorder have had their lives transformed by a single treatment of a breakthrough gene-editing therapy, according to the lead researcher of the trial published in the New England Journal of Medicine.
The patients from New Zealand, the Netherlands and the UK have hereditary angioedema, a genetic disorder characterised by severe, painful and unpredictable swelling attacks. These interfere with daily life and can affect airways and prove fatal.
Now researchers from the University of Auckland, Amsterdam University Medical Center and Cambridge University Hospitals have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.
“It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients’ very disabling symptoms,” says principal investigator Dr Hilary Longhurst, who is both a clinical immunologist at Auckland Hospital Te Toku Tumai and an honorary associate professor at the University of Auckland.
“Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders.”
Globally, it is estimated one in 50 000 people have hereditary angioedema, however, because it is rare, it is often not correctly diagnosed.
In the Phase 1 study, there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision from late 2021 and onwards.
The investigational therapy, called NTLA-2002, utilises in vivo CRISPR/Cas9 technology to target the KLKB1 gene, which is responsible for producing plasma prekallikrein.
By editing this gene, the therapy reduces the levels of total plasma kallikrein, effectively preventing angioedema (swelling) attacks. The trial demonstrated dose-dependent reduction in total plasma kallikrein protein with reductions of up to 95% achieved. A mean reduction of 95% in angioedema attacks was observed across all patients through to the latest follow-up.
The patients from the initial study will be followed up for a further 15 years to continue to assess long-term safety and efficacy.
A larger and more robust, double-blinded, placebo-controlled phase two trial is under way and a Phase 3 trial is planned to start in the second half of 2024.
Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center says these promising results are a step forward for this group of patients.
“We’ve never been closer to the ultimate treatment goal of normalising hereditary angioedema patients’ lives and offering total control of the disease,” says Dr Cohn.
Dr Padmalal Gurugama, consultant in clinical immunology and allergy at Cambridge University Hospitals, UK says the gene editing therapy has the potential to significantly improve patients’ lives.
“Hereditary angioedema can cause patients severe swellings and intense pain which can be life-threatening as well as restricting normal activities, such as going to work or school.
“Because it is often misdiagnosed, many patients undergo unnecessary treatments and invasive procedures.”
The therapy affects only the patient and is not passed onto their children, who still have an even chance of inheriting the disorder.
The studies have been funded by US company Intellia Therapeutics, which chose New Zealand to lead the research as, at that time (late 2021) it had relatively fewer COVID cases than other countries.
So far, the only approved CRISPR therapy, CASGEVY, is for sickle cell disease and beta thalassemia.
However, CASGEVY is an ex vivo CRISPR therapy, where the cells are taken from the patient and edited outside of the body and then reinfused, whereas NTLA-2002 is an in vivo CRISPR therapy, where the targeted gene editing occurs directly within the body.
CRISPR technologies are being used to develop treatment for a wide range of diseases, such as genetic disease, cardiovascular disease, cancer and autoimmune diseases.
CRISPR-Cas9 is a customisable tool that lets scientists cut and insert small pieces of DNA at precise areas along a DNA strand. This lets scientists study our genes in a specific, targeted way.
Credit: Ernesto del Aguila III, National Human Genome Research Institute, NIH
Researchers from the Karolinska Institutet in Sweden have identified potential pitfalls in the use of the gene editing technique CRISPR-Cas9, a gene scissors that is used for cancer treatments. Their findings are published in Life Science Alliance.
The study has identified that a cancer cell line, derived from leukaemia, removes a region that encodes a tumour-suppressing gene and genes that control cell growth.
“We found that this elimination often occurs when cancer cells are exposed to stress, such as when using CRISPR, gene scissors, or other treatments such as antibiotics. The elimination changes gene regulation in a unique way, which in turn affects basic biological processes such as DNA replication, cell cycle regulation, and DNA repair,” says Claudia Kutter, research group leader at the Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet.
This knowledge is important for researchers, clinicians, and biotechnologists to correctly interpret and apply gene editing results. The study also has clinical relevance, as the observed eliminations are in genes associated with cancer, which has implications for cancer research and treatment.
“Shockingly, this elimination has been unintentionally overlooked by many researchers who modify genes in cancer cells by CRISPR screenings. The elimination also occurred more frequently in patients who have undergone cancer treatment. The treated cancer cells had, due to the elimination, a selective advantage, which is bad for the patient’s long-term survival as these cells remained after the treatment,” says Claudia.
“The study mainly serves as a warning signal, but also opens doors for further research aimed at harnessing the potential of gene editing while minimising unintended consequences,” Claudia concludes.
Researchers have shown that nose drops of genetically modified ‘friendly’ bacteria protect against a form of meningitis.
The study, published in the journal Science Translational Medicine, was led by Professor Robert Read and Dr Jay Laver from the NIHR Southampton Biomedical Research Centre and the University of Southampton, and is the first of its kind.
The researchers spliced a gene into a harmless bacteria type, which enabled it to remain in the nose for longer than normal, triggering an immune response. Then, via nose drops, they administered these altered bacteria into the noses of healthy volunteers. The results showed a strong immune response against bacteria that cause meningitis and long-lasting protection.
Meningitis protection
Meningitis occurs in people of all age groups but affects mainly infants, young children and the elderly. Meningococcal meningitis, a bacterial form of the disease, can lead to death in as little as four hours after symptom onset.
Around 10% of adults carry Neisseria meningitidis in the back of their nose and throat without any signs or symptoms. In certain people however, it can invade the bloodstream, potentially leading to life-threatening conditions including meningitis and septicaemia.
The ‘friendly’ bacteria Neisseria lactamica also lives in some people’s noses naturally. By occupying the nose, it denies a foothold to its close relative N. meningitidis.
Boosted immune response
The study is an extension of the team’s previous work aiming to exploit this natural phenomenon. Nose drops of N. lactamica in that previous study prevented N. meningitidis from settling in 60% of participants. The team sought to improve on this.
They gave N. lactamica one of N. meningitidis’ key weapons; by giving it the gene for a ‘sticky’ surface protein that grips the cells lining the nose. Those modified bacteria managed to remain longer and produced a stronger immune response. From at least 28 days, most participants (86%) still carried it at 90 days, it caused no adverse symptoms.
This is a promising find for this new way of preventing life-threatening infections, without drugs, especially in the face of growing antimicrobial resistance.
Dr Jay Laver, Senior Research Fellow in Molecular Microbiology at the University of Southampton, commented: “Although this study has identified the potential of our recombinant N. lactamica technology for protecting people against meningococcal disease, the underlying platform technology has broader applications.
“It is theoretically possible to express any antigen in our bacteria, which means we can potentially adapt them to combat a multitude of infections that enter the body through the upper respiratory tract. In addition to the delivery of vaccine antigens, advances in synthetic biology mean we might also use genetically modified bacteria to manufacture and deliver therapeutics molecules in the near future.”
Prof Read, Director of the NIHR Southampton Biomedical Research Centre said: “This work has shown that it is possible to protect people from severe diseases by using nose drops containing genetically modified friendly bacteria. We think this is likely to be a very successful and popular way of protecting people against a range of diseases in the future.”
