Category: Genetics

Categories : GeneticsTags :

Genomic ‘Butterfly Effect’ Explains Risk for Autism spectrum Disorder

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Photo by Sangharsh Lohakare on Unsplash

Researchers in Japan discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to autism spectrum disorder (ASD). In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighbouring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics.

ASD is a group of conditions characterised in part by repetitive behaviours and difficulties in social interaction. Although it runs in families, the genetics of its heritability are complex and remain only partially understood. Studies have shown that the high degree of heritability cannot be explained simply by looking at the part of the genome that codes for proteins. Rather, the answer could lie in the non-coding regions of the genome, particularly in promoters, the parts of the genome that ultimately control whether or not the proteins are actually produced. The team led by Atsushi Takata at in the RIKEN Center for Brain Science (CBS) examined de novo gene variants (new, non-inherited mutations) in these parts of the genome.

The researchers analysed an extensive dataset of over 5000 families, making this one of the world’s largest genome-wide studies of ASD to date. They focused on TADs – three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren’t located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.

“Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome,” says Takata.

To confirm this, the researchers edited the DNA of stem cells using the CRISPR/Cas9 system, making mutations in specific promoters. As expected, they observed that a single genetic change in a promotor caused alterations in an ASD-associated gene within the same TAD. Because numerous genes linked to ASD and neurodevelopment were also affected in the mutant stem cells, Takata likens the process to a genomic “butterfly effect” in which a single mutation dysregulates disease-associated genes that are scattered in distant regions of the genome.

Takata believes that this finding has implications for the development of new diagnostic and therapeutic strategies. “At the very least, when assessing an individual’s risk for ASD, we now know that we need to look beyond ASD-related genes when doing genetic risk assessment, and focus on whole TADs that contain ASD-related genes,” explains Takata. “Further, an intervention that corrects aberrant promoter-enhancer interactions caused by a promotor mutation may also have therapeutic effects on ASD.”

Further research involving more families and patients is crucial for better understanding ASD’s genetic roots. “By expanding our research, we will gain a better understanding of the genetic architecture and biology of ASD, leading to clinical management that enhances the well-being of affected individuals, their families, and society,” says Takata.

Source: RIKEN

Categories : Cardiovascular Disease GeneticsTags :

Study Finds New Genetic Markers for Blood Pressure

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NIH-led study finds genetic markers that explain up to 12% of the differences between two people’s blood pressure.

Photo by CDC on Unsplash

National Institutes of Health researchers and collaborators have discovered over 100 new regions of the human genome, also known as genomic loci, that appear to influence a person’s blood pressure. Results of the study also point to several specific genomic loci that may be relevant to iron metabolism and a type of cellular receptor known as adrenergic receptors. 

The study, published in Nature Genetics, is one of the largest such genomic studies of blood pressure to date, including data from over 1 million participants and laying the groundwork for researchers to better understand how blood pressure is regulated. Such insights could point to potential new drug targets. 

“Our study helps explain a much larger proportion of the differences between two people’s blood pressure than was previously known,” said first author Jacob Keaton, PhD. “Our study found additional genomic locations that together explain a much larger part of the genetic differences in people’s blood pressure. Knowing a person’s risk for developing hypertension could lead to tailored treatments, which are more likely to be effective.” 

Hypertension often runs in families, meaning that there is a genetic component to developing the condition in addition to environmental contributions such as a high-salt diet, lack of exercise, smoking and stress.

To understand the genetics of blood pressure, the researchers combined four large datasets from genome-wide association studies of blood pressure and hypertension. After analysing the data, they found over 2000 genomic loci linked to blood pressure, including 113 new regions. Among the newly discovered genomic loci, several reside in genes that play a role in iron metabolism, confirming previous reports that high levels of accumulated iron can contribute to cardiovascular disease.  

The researchers also confirmed the association between variants in the ADRA1A gene and blood pressure. ADRA1A encodes a type of cell receptor, called an adrenergic receptor, that is currently a target for blood pressure medication, suggesting that other genomic variants discovered in the study may also have the potential to be drug targets to alter blood pressure. 

“This study shows that these big genome-wide association studies have clinical relevance for finding new drug targets and are needed to discover more drug targets as we go forward,” said Dr Keaton. 

From these analyses, the researchers were able to calculate a polygenic risk score, which combines the effects of all genomic variants together to predict blood pressure and risk for hypertension. These risk scores consider which genomic variants confer risk for hypertension and reveal clinically meaningful differences between people’s blood pressure. 

Polygenic risk scores have potential to serve as a useful tool in precision medicine, but more diverse genomic data is needed for them to be applicable broadly in routine health care. While the collected data was mostly from people of European ancestry, the polygenic risk scores were also applicable to people of African ancestry.

Source: National Institutes of Health

Categories : Cardiovascular Disease GeneticsTags :

Rare Longevity Mutation may Also Reduce Cardiovascular Disease Risk

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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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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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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