Category: Genetics

Categories : Cardiovascular Disease GeneticsTags :

Rare Longevity Mutation may Also Reduce Cardiovascular Disease Risk

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Photo by Sangharsh Lohakare on Unsplash

People with a rare longevity condition known as growth hormone receptor deficiency (GHRD) may also have possible cardiovascular health advantages. Also called Laron syndrome, GHRD, which is characterised by the body’s impaired ability to use its own growth hormone and results in stunted growth, has been linked in mice to a record 40% longevity extension and lower risks for various age-related diseases.

The risk of cardiovascular disease in individuals with GHRD has remained unclear until now, leading to the speculation that in people, this mouse longevity mutation may actually increase cardiovascular disease. In humans, unlike mice, GHRD is not associated with an extended lifespan.

The study, appearing in Med, is the latest product of an international collaboration spanning nearly 20 years between Valter Longo, professor of gerontology at the USC Leonard Davis School of Gerontology, and endocrinologist Jaime Guevara-Aguirre of the Universidad San Francisco de Quito, Ecuador.

Over the past two decades, Longo, Guevara-Aguirre and colleagues have examined the health and aging of people with the gene mutation that causes GHRD. This rare mutation, found in just 400 to 500 people worldwide, was identified in a group of Ecuadorians whose ancestors had fled Spain during the Inquisition more than three centuries ago. The mutation leaves them with ineffective growth hormone receptors and results in a type of dwarfism.

The team’s previous research has indicated that while GHRD/Laron syndrome reduces growth, it also appears to reduce the risk of several age-related diseases. Although the Ecuadorians with GHRD have a higher rate of obesity, they have a very low risk of cancer and Type 2 diabetes. They also appear to have healthier brains and better performance on tests of cognition and memory.

For the current study, the research team examined cardiovascular function, damage, and risk factors in GHRD subjects and their relatives. Researchers conducted two phases of measurements in Los Angeles and Ecuador, involving a total of 51 individuals, with 24 diagnosed with GHRD and 27 relatives without GHRD serving as controls.

Key findings from the study included:

  • GHRD subjects displayed lower blood sugar, insulin resistance, and blood pressure compared to the control group.
  • They also had smaller heart dimensions and similar pulse wave velocity (a measure of stiffness in the arteries) but had lower carotid artery thickness compared to control subjects.
  • Despite elevated low-density lipoprotein (LDL) levels, GHRD subjects showed a trend for lower carotid artery atherosclerotic plaques compared to controls (7% vs 36%).

“These findings suggest that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors compared to their relatives,” said Longo, senior author of the new study. “Although the population tested is small, together with studies in mice and other organisms this human data provide valuable insights into the health effects of growth hormone receptor deficiency and suggest that drugs or dietary interventions that cause similar effects could reduce disease incidence and possibly extend longevity.”

Source: University of Southern California

Categories : COVID GeneticsTags :

Key Gene may Protect Against Severe COVID Infections in Men Under 75

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A certain variant of a key anti-inflammatory gene protects men under age 75 from severe illness and death when hospitalised from COVID, a genetic analysis of their blood shows. According to the authors of a major study published in The Journal of Infectious Diseases, the protective gene in question, an interleukin-1 receptor antagonist (IL1RN) variant, appears to tamp down inflammation, which can get out of control in severe cases SARS-CoV-2 infection.

The study showed that 124 men between the ages of 19 and 74 who possessed the IL1RN variant, called rs419598, were less likely to become severely ill after hospitalisation for COVID, and 80% less likely to die from the disease.

IL1RN is expressed naturally in the body. Different types of interleukin genes are known to dial inflammation up or down in the context of arthritis, and researchers say the results of the current study suggest that a similar dynamic influences the interleukin-1-related inflammation seen in COVID patients.

The findings, from researchers at NYU Grossman School of Medicine, stand out because historically more men than women are known to die from COVID, and the IL1RN rs419598 variant appears to selectively protect only men up to age 74, but not beyond that as age-related chronic illnesses unfold.

The research team used sequencing technologies for the study to determine the presence of specific genes or variations in the letter code that makes up genes in blood samples from 2589 men and women hospitalised for COVID at NYU Langone’s Tisch Hospital in Manhattan from March 2020 to March 2021.

More than half of the men and women in the study were older than age 60 and obese, factors that are known to increase the risk of death from the viral infection. Overall, more men than women (240 men, at 60.5%; and 157 women, at 39.5%) died from their disease, with women 20% less likely to die than men.

“Our study results show that among hospitalised patients, while women are still overall less likely than men to die from COVID-19, those men age 74 and younger who possess the IL1RN gene variant rs419598 are much less likely to suffer the severe inflammation tied to SARS-CoV-2 infection and less likely to die from the disease,” said study colead investigator and molecular biologist Mukundan Attur, PhD. Attur is an associate professor in the Department of Medicine at NYU Langone Health.

Among the study’s other findings was that average blood levels of the anti-inflammatory protein IL-1Ra, coded by IL1RN, were 14 times higher in 181 hospitalised men than in healthy male study controls from the general population, and 10 times as high in 178 hospitalised women than in healthy females. The increased levels of IL-1Ra in women did not result in any statistically significant mortality reductions.

“Our analysis offers substantial evidence of the biological link between the severe inflammation seen in SARS-CoV-2 and that which occurs in rheumatoid arthritis,” said study senior investigator Steven Abramson, MD, the Frederick H. King Professor of Internal Medicine at NYU Langone.

Abramson, a rheumatologist who also serves as chair of the Department of Medicine and chief academic officer at NYU Langone, says previous research has shown that such rheumatoid inflammation is lower in people who possessed one of the three IL1RN variants analysed in the study.

More importantly, Abramson says, the new research suggests that restraining the interleukin-1 biological pathway, which is in part tamped down by the anti-inflammatory protein IL-1Ra, could help prevent the severe inflammation seen in SARS-CoV-2 infection. Further research, he says, is warranted into whether IL-1-inhibiting therapies, such as the IL1 receptor antagonists anakinra, canakinumab, and rilonacept, are effective against Covid infection.

Abramson already has plans to investigate if the IL-1 pathway plays a role in long Covid, when people experience new or lingering symptoms, such as fatigue and ‘brain fog’, months after recuperating from their initial infection.

Abramson points out that the new study adds to the growing scientific evidence about the biological factors that contribute to gender differences seen in deaths from COVID, which are known to vary widely across the United States.

Source: NYU Langone Health / NYU Grossman School of Medicine

Categories : GeneticsTags :

New Genetic Tool Predicts Unintentional Mutations from CRISPR Edits

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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.”

Source: University of California – San Diego

Categories : Genetics Metabolic DisordersTags :

Smart Moo-ve for Diabetes Treatment: Insulin Produced in Cow’s Milk

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An unassuming brown bovine from the south of Brazil has made history as the first transgenic cow capable of producing human insulin in her milk. The advancement, led by researchers from the University of Illinois Urbana-Champaign and the Universidade de São Paulo, could herald a new era in insulin production, one day eliminating drug scarcity and high costs for people living with diabetes.

“Mother Nature designed the mammary gland as a factory to make protein really, really efficiently. We can take advantage of that system to produce a protein that can help hundreds of millions of people worldwide,” said Matt Wheeler, professor in the Department of Animal Sciences, part of the College of Agricultural, Consumer and Environmental Sciences (ACES) at U. of I.

Wheeler is lead author on a new Biotechnology Journal study describing the development of the insulin-producing cow, a proof-of-concept achievement that could be scaled up after additional testing and FDA approval.

Precise insertion of DNA

Wheeler’s colleagues in Brazil inserted a segment of human DNA coding for proinsulin – the protein precursor of the active form of insulin – into cell nuclei of 10 cow embryos. These were implanted in the uteruses of normal cows in Brazil, and one transgenic calf was born. Thanks to updated genetic engineering technology, the human DNA was targeted for expression – the process whereby gene sequences are read and translated into protein products – in mammary tissue only.

“In the old days, we used to just slam DNA in and hope it got expressed where you wanted it to,” Wheeler said. “We can be much more strategic and targeted these days. Using a DNA construct specific to mammary tissue means there’s no human insulin circulating in the cow’s blood or other tissues. It also takes advantage of the mammary gland’s capabilities for producing large quantities of protein.”

When the cow reached maturity, the team unsuccessfully attempted to impregnate her using standard artificial insemination techniques. Instead, they stimulated her first lactation using hormones. The lactation yielded milk, but a smaller quantity than would occur after a successful pregnancy. Still, human proinsulin and, surprisingly, insulin were detectable in the milk.

“Our goal was to make proinsulin, purify it out to insulin, and go from there. But the cow basically processed it herself. She makes about three to one biologically active insulin to proinsulin,” Wheeler said. “The mammary gland is a magical thing.”

The insulin and proinsulin, which would need to be extracted and purified for use, were expressed at a few grams per liter in the milk. But because the lactation was induced hormonally and the milk volume was smaller than expected, the team can’t say exactly how much insulin would be made in a typical lactation.

Conservatively, Wheeler says if a cow could make 1 gram of insulin per liter and a typical Holstein makes 40 to 50 litres per day, that’s a lot of insulin. Especially since the typical unit of insulin equals 0.0347 milligrams.

“That means each gram is equivalent to 28,818 units of insulin,” Wheeler said. “And that’s just one liter; Holsteins can produce 50 liters per day. You can do the math.”

The team plans to re-clone the cow, and is optimistic they’ll achieve greater success with pregnancy and full lactation cycles in the next generation. Eventually, they hope to create transgenic bulls to mate with the females, creating transgenic offspring that can be used to establish a purpose-built herd. Wheeler says even a small herd could quickly outcompete existing methods – transgenic yeast and bacteria – for producing insulin, and could do so without having to create highly technical facilities or infrastructure.

“With regard to mass-producing insulin in milk, you’d need specialized, high-health-status facilities for the cattle, but it’s nothing too out of the ordinary for our well-established dairy industry,” Wheeler said. “We know what we’re doing with cows.”

An efficient system to collect and purify insulin products would be needed, as well as FDA approval, before transgenic cows could supply insulin for the world’s diabetics. But Wheeler is confident that day is coming.

“I could see a future where a 100-head herd, equivalent to a small Illinois or Wisconsin dairy, could produce all the insulin needed for the country,” he said. “And a larger herd? You could make the whole world’s supply in a year.

Source: University of Illinois College of Agricultural, Consumer and Environmental Sciences

Categories : GeneticsTags :

First DNA Study of Ancient Eastern Arabians Reveals Malaria Adaptation

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Photo by MJ RAHNAMA

People living in ancient Eastern Arabia appear to have developed resistance to malaria following the appearance of agriculture in the region around five thousand years ago, a new study published its in Cell Genomics reveals.

DNA analysis of the remains of four individuals from Tylos-period Bahrain (300 BCE to 600 CE) – the first ancient genomes from Eastern Arabia – revealed the malaria-protective G6PD Mediterranean mutation in three samples.

The discovery of the G6PD Mediterranean mutation in ancient Bahrainis suggests that many people in the region’s ancient populations may have enjoyed protection from malaria.

In the present day, among the populations examined, the G6PD mutation is detected at its peak frequency in the Emirates, the study indicates.

Researchers discovered that the ancestry of Tylos-period inhabitants of Bahrain comprises sources related to ancient groups from Anatolia, the Levant and Caucasus/Iran.

The four Bahrain individuals were genetically more like present-day populations from the Levant and Iraq than to Arabians.

Experts from Liverpool John Moores University, the University of Birmingham Dubai, and the University of Cambridge worked with the Bahrain Authority for Culture and Antiquities and other Arabian institutes such as the Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, as well as research centres in Europe.

Lead researcher Rui Martiniano, from Liverpool John Moores University, commented: “According to our estimates, the G6PD Mediterranean mutation rose in frequency around five-to-six thousand years ago — coinciding with the onset of agriculture in the region, which would have created ideal conditions for the proliferation of malaria.”

Due to poor ancient DNA preservation in hot and humid climates, no ancient DNA from Arabia has been sequenced until now — preventing the direct examination of the genetic ancestry of its past populations.

Marc Haber, from the University of Birmingham Dubai, commented: “By obtaining the first ancient genomes from Eastern Arabia, we provide unprecedented insights into human history and disease progression in this region. This knowledge goes beyond historical understanding, providing predictive capabilities for disease susceptibility, spread, and treatment, thus promoting better health outcomes.”

“The rich population history of Bahrain, and more generally of Arabia, has been severely understudied from a genetic perspective. We provide the first genetic snapshot of past Arabian populations – obtaining important insights about malaria adaptation, which was historically endemic in the region,” commented Fatima Aloraifi, from the Mersey and West Lancashire NHS Trust.

Salman Almahari, Director of Antiquities and Museums at the Bahrain Authority for Culture and Antiquities, states, “Our study also paves the way for future research that will shed light on human population movements in Arabia and other regions with harsh climates where it is difficult to find well-preserved sources of DNA.”

Data gathered from the analysis of the four individuals’ remains allowed researchers to characterise the genetic composition of the region’s pre-Islamic inhabitants – insights that could only have been obtained by directly examining ancient DNA sequences.

Researchers collected ancient human remains from archaeological collections stored at the Bahrain National Museum, gathering DNA from 25 of them. Only four samples were sequenced to higher coverage due to poor preservation.

The finding of malaria adaptation agrees with archaeological and textual evidence that suggested malaria was historically endemic in Eastern Arabia, whilst the DNA ancestry of Tylos-period inhabitants of Bahrain corroborates archaeological evidence of interactions between Bahrain and neighbouring regions.

Source: University of Birmingham

Categories : GeneticsTags :

Single Gene-editing Therapy Slashes Symptoms of Hereditary Disorder by 95%

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Source: Pixabay CC0

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.

Source: University of Auckland

Categories : Genetics PaediatricsTags :

Gene Identified for Rare Disorder Involving Extra Fingers and Toes

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Photo by Jonathan Borba on Unsplash

A rare disorder which causes babies to be born with extra fingers and toes and a range of birth defects has been identified in new research published in the American Journal of Human Genetics. The disorder, which has not yet been named, is caused by a genetic mutation in a gene called MAX.

As well as extra digits – polydactyly — it leads to a range of symptoms relating to ongoing brain growth, such as autism. The research marks the first time this genetic link has been identified. It has also found a molecule that could potentially be used to treat some of the neurological symptoms and prevent any worsening of their condition. However, more research is needed to test this molecule before it can be used as a treatment.

Co-led by the University of Leeds, the study focuses on three individuals with a rare combination of physical traits, namely polydactyly, and a much larger than average head circumference – known as macrocephaly.

The individuals share some other characteristics, including delayed development of their eyes which results in problems with their vision early in life.

The researchers compared the DNA of these individuals and found they all carried the shared genetic mutation causing their birth defects.

The latest research was co-led by Dr James Poulter from the University of Leeds; Dr Pierre Lavigne at Université de Sherbrooke in Québec and Professor Helen Firth at Cambridge University.

As with many rare disorders, the disorder currently has no treatments – but in this case, the researchers identified one already undergoing clinical trials which might reverse some of the mutation’s effects.

The study team has highlighted the importance of interdisciplinary research into rare diseases in giving understanding and hope of a treatment to families who often face many years of uncertainty about their child’s condition and prognosis.

The researchers now plan to look for additional patients with mutations in MAX to better understand the disorder and investigate whether the potential treatment improves the symptoms caused by the mutation.

Source: University of Leeds

Categories : Genetics PaediatricsTags :

Gene Therapy Restores Hearing in Children with Hereditary Deafness

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Photo by jonas mohamadi

A new study co-led by investigators from Mass Eye and Ear, a member of Mass General Brigham, demonstrated the effectiveness of a gene therapy towards restoring hearing function for children suffering from hereditary deafness.

In a trial of six children taking place at the Eye & ENT Hospital of Fudan University in Shanghai, China, the researchers found the novel gene therapy to be an effective treatment for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9. With its first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for treating this condition, with the most patients treated and longest follow-up to date. Their results are published in The Lancet.

“If children are unable to hear, their brains can develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School. “The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”

Hearing loss affects more than 1.5 billion people worldwide, with congenital deafness making up about 26 million of those individuals. For hearing loss in children, more than 60% stem from genetic reasons. DFNB9 for example, is a hereditary disease caused by mutations of the OTOF gene and a failure to produce a functioning otoferlin protein, which is necessary for the transmission of the sound signals from the ear to the brain. There are currently no FDA-approved drugs to help with hereditary deafness, which has opened the door for new solutions like gene therapies.

In order to test this novel treatment, six children with DFNB9 were observed over a 26-week period at the Eye & ENT Hospital of Fudan University. The Mass Eye and Ear collaborators utilised an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into the inner ears of the patients through a special surgical procedure. Differing doses of the single injection of the viral vector were used.

All six children in the study had total deafness, as indicated by an average auditory brainstem response (ABR) threshold of over 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a 40-57 decibel reduction in ABR testing, dramatic improvements in speech perception and the restored ability to conduct normal conversation. Overall, no dose-limiting toxicity was observed. While following up on the patients, 48 adverse events were observed, with a significant majority (96%) being low grade, and the rest being transitory with no long-term impact.

Trial findings will also be presented February 3rd at the Association for Research in Otolaryngology Annual Meeting.

This study provides evidence towards the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss. Moreover, the results contribute to an understanding of the safety of AAV insertion into the human inner ear. In regard to the usage of AAVs, the success of a dual-AAV vector carrying two pieces of the OTOF gene is notable. Typically, AAVs have a gene size limit, and so for a gene like OTOF that exceeds that limit, the achievement with a dual viral vector opens the door for AAV’s use with other large genes that are typically too big for the vector.

“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9,” said lead study author Yilai Shu, MD, of the Eye & ENT Hospital of Fudan University at Fudan University. Shu previously served as a postdoctoral fellow in Chen’s lab at Mass Eye and Ear. “I am truly excited about our future work on other forms of genetic hearing loss to bring treatments to more patients.”

The researchers plan to expand the trial to a larger sample size as well as track their outcomes over a longer timeline.

“Not since cochlear implants were invented 60 years ago, has there been an effective treatment for deafness,” said Chen. “This is a huge milestone that symbolises a new era in the fight against all types of hearing loss.”

Source: Massachusetts Eye and Ear Infirmary

Categories : Cancer GeneticsTags :

mRNA Technology Restores Tumour Suppressor Protein in Ovarian Cancer

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Using mRNA technology developed and matured for certain COVID vaccines, researchers have successfully restored the tumour-suppressing p53 protein in mouse models of advanced human ovarian cancer, significantly extending their survival. They report their results in Cancer Communications.

Ovarian cancer is often only detected at an advanced stage and metastases have already formed — usually in the intestines, abdomen or lymph nodes. At such a late stage, only 20 to 30% of all those affected survive the next five years. “Unfortunately, this situation has hardly changed at all over the past two decades,” says Professor Klaus Strebhardt, Director of the Department of Molecular Gynecology and Obstetrics at University Hospital Frankfurt.

In 96% of all ovarian cancer (high-grade) patients, the tumour suppressor gene p53 has mutated and is now non-functional. The gene contains the building instructions for an important protein that normally recognises damage in each cell’s DNA. It then prevents these abnormal cells from proliferating and activates repair mechanisms that rectify the damage.

If this fails, it induces cell death. “In this way, p53 is very effective in preventing carcinogenesis,” explains Strebhardt. “But when it is mutated, this protective mechanism is eradicated.”

If a cell wants to produce a certain protein, it first makes a transcript of the gene containing the building instructions for it. Such transcripts are called mRNAs. In women with ovarian cancer, the p53 mRNAs are just as defective as the gene from which they were copied.

“We produced an mRNA in the laboratory that contained the blueprint for a normal, non-mutated p53 protein,” says Dr Monika Raab from the Department of Molecular Gynecology and Obstetrics, who conducted many of the key experiments in the study.

“We packed it into small lipid vesicles, known as liposomes, and then tested them first in cultures of various human cancer cell lines. The cells used the artificial mRNA to produce functional p53 protein.”

In the next step, the scientists cultivated ovarian tumours – organoids – from patient cells sourced by the team led by Professor Sven Becker, Director of the Women’s Clinic at University Hospital Frankfurt.

After treatment with the artificial mRNA, the organoids shrank and began to die.

To test whether the artificial mRNA is also effective in organisms and can combat metastases in the abdomen, the researchers implanted human ovarian tumour cells into the ovaries of mice and injected the mRNA liposomes into the animals some time later.

The result was very convincing, says Strebhardt: “With the help of the artificial mRNA, cells in the animals treated produced large quantities of the functional p53 protein, and as a result both the tumours in the ovaries and the metastases disappeared almost completely.”

That the method was so successful is partly due to recent advances in mRNA technology: Normally, mRNA transcripts are very sensitive and degraded by cells within minutes.

However, it is meanwhile possible to prevent this by specifically modifying the molecules.

This extends their lifespan substantially, in this study to up to two weeks.

In addition, the chemical composition of the artificial mRNA is slightly different to that of its natural counterpart.

This prevents the immune system from intervening after the molecule has been injected and from triggering inflammatory responses.

In 2023, the Hungarian scientist Katalin Karikó and her American colleague Drew Weissman were awarded the Nobel Prize in Physiology or Medicine for this discovery.

“Thanks to the development of mRNA vaccines such as those of BioNTech and Moderna, which went into action during the SARS-CoV-2 pandemic, we now also know how to make the molecules even more effective,” explains Strebhardt.

Strebhardt, Raab and Becker are now looking for partners to join the next step of the translational project: testing on patients with ovarian cancer. “What is crucial now is the question of whether we can implement the concept and the results in clinical reality and use our method to help cancer patients,” says Strebhardt. The latest results make him very optimistic that the tide could finally turn in the treatment of ovarian carcinomas. “p53 mRNA is not a normal therapeutic that targets a specific weak point in cancer cells. Instead, we are repairing a natural mechanism that the body normally uses very effectively to suppress carcinogenesis. This is a completely different quality of cancer therapy.”

Source: Goethe University Frankfurt

Categories : Genetics UncategorizedTags :

Dual Testosterone Blockers More Effective in Treating Prostate Cancer

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Credit: Darryl Leja National Human Genome Research Institute National Institutes Of Health

Combining testosterone-blocking drugs in patients with prostate cancer relapse prevents the spread of cancer better than treatment with a single drug, a multi-institution, Phase 3 clinical trial led by UC San Francisco researchers has found.

The approach can extend the time between debilitating drug treatments without prolonging the time it takes to recover from each treatment.

Prostate cancer affects 1 in 8 men, and is usually treated with one of several testosterone-lowering drugs for a set period of time.

“This adds to a growing body of evidence in favour of more intensive testosterone-blocking therapy in patients with higher-risk prostate cancer,” said Rahul Aggarwal, MD, professor in the UCSF School of Medicine and lead author of the paper.

The researchers’ findings were published in the Journal of Clinical Oncology. They were first announced in September 2022 at the annual meeting of the European Society for Medical Oncology.

A case for intensifying prostate cancer treatment

The new study focused on patients who had surgery for prostate cancer, and yet the cancer relapsed and was detected through a sudden jump in the blood levels of a protein called prostate-specific antigen (PSA).

“We looked at patients who had a fast rise in their PSA – an indicator of a higher-risk form of relapsed prostate cancer,” Aggarwal said.

“Our goal was to test several different hormone therapy strategies to find the best approach in terms of delaying the cancer’s progression.”

Between 2017 and 2022, 503 patients were randomly assigned to take a single testosterone-lowering therapy chosen by their oncologist, or to combine it with one or two other testosterone-lowering drugs.

The additional drugs were already FDA-approved for other cancers but hadn’t been tested in this way with prostate cancer.

The patients stayed on the assigned therapy for a year. Whether given singly or in combination, the drugs caused their testosterone to plummet.

That put the brakes on their cancer but also caused fatigue, hot flashes, decreased libido and other problems for patients, according to Aggarwal.

Compared to the prostate cancer patients who only received a single drug therapy during their year of treatment, patients who received either one or two additional drugs stayed cancer-free, with low PSA levels, for longer.

Once off the treatment, patients who took the combination therapies saw their testosterone levels recover just as fast as others who took the single drug.

The researchers are following up with a more detailed analysis of how patients fared on the different treatments – which side effects they experienced and for how long, and how they felt overall as they recovered.

“New cancer therapies must clear a high bar to make their way to patients,” Aggarwal said. “With the evidence in this study and others, combination hormone therapy should be considered a standard of care in prostate cancer patients with high-risk relapse after prior treatment.”

Source: University of California – San Francisco