In a new JAMA Dermatology study, scientists at King’s found that changes in two parts of the genome work together to influence alopecia risk.
Frontal fibrosing alopecia (FFA) is a highly distressing dermatological disorder which is associated with inflammation, scarring and irreversible hair loss. The disease affects an increasing number of patients worldwide and is caused by genetic and environmental factors.
The study authors conducted a meta-analysis of four cohorts of women with FFA across the UK and Europe. When looking into a cluster of immune genes known as the major histocompatibility complex, which help immune systems recognise foreign substances, they identified specific genetic differences that interact with ERAP1 and increase the risk of developing FFA.
This gene-gene interaction is a rare phenomenon in human genetics, known as “epistasis”. This means that the risk associated with one gene is modified by another gene. Different versions of the two genes involved in this interaction have been observed in some other autoimmune diseases, including psoriasis and ankylosing spondylitis.
Previous research has identified that genetic variants in the ERAP1 and ERAP2 genes were associated with survival of the Black Death, a bubonic plague which swept through Europe in the mid-1300s. Such genetic variants, which are associated with protection from infection, may also make people more prone to certain immune conditions. This new study demonstrates that this is the case for FFA.
“Our study is the largest ever genome-wide association study into frontal fibrosing alopecia (FFA), an inflammatory and scarring condition affecting almost exclusively women,” said Dr Christos Tziotzios, Senior Lecturer of the St John’s Institute of Dermatology at King’s and Consultant Dermatologist at Guy’s and St Thomas’ NHS Foundation Trust
He added: “Since the disease was described in 1994, the number of people affected has increased dramatically. Our newest finding sheds more light into the autoimmune basis of the condition and provides direction for further research into drug development.”
As well as improving our understanding of the genetic factors that drive FFA, the authors hope that these findings can be applied to predict risk of its development while paving the way for new treatments.
The team of scientists are now investigating the prospect of predictive genetic test for FFA risk, while exploring the potential of targeting ERAP1 with highly specific drugs as a new way of treating this condition.
Expert panel’s findings refute attribution of sudden death to sickle cell trait
Photo by National Cancer Institute on Unsplash
A systematic literature review found no evidence to support that physical exertion without rhabdomyolysis (muscle breakdown) or heat injury can cause sudden death for individuals with sickle cell trait (SCT), nor is there any high-level evidence that SCT causes acute pain crises. These results were published in the American Society of Hematology’s flagship journal, Blood, and informed the Society’s updated position statement on SCT.
“SCT has long been misunderstood, fuelling widespread misinformation and medically inaccurate claims that it can lead to sudden death. This misconception has been especially prominent in cases of Black men with SCT,” said Belinda Avalos, MD, ASH president. “In light of the pervasive, widely publicized, and harmful nature of this myth, the Society aims to further promote accurate information to protect and empower affected communities.”
Individuals with SCT have one copy of the gene associated with sickle cell disease (SCD). SCD is a blood disorder characterised by misshapen blood cells that can cause blockages, leading to infections and episodes of severe pain, often referred to as acute pain crises. Unlike SCD, SCT – which affects over 100 million people worldwide, including 8 to 10% of Black Americans – is not a disease. Individuals with SCT do not go on to develop SCD and generally do not experience any related health complications.
“To date, this is the most authoritative and definitive systematic review on this subject,” said study author Michael R. DeBaun, MD, MPH, professor of pediatrics and medicine at Vanderbilt University School of Medicine and founder and director of the Vanderbilt-Meharry Sickle Cell Disease Center of Excellence. “This review shows that any primary, secondary, or tertiary cause of death attributable to SCT is not a diagnosis substantiated by the medical evidence.”
ASH convened an expert panel of hematologists and forensic pathologists to systematically review all existing available research to answer two primary questions: 1) Do uncomplicated acute pain crises occur in people with SCT? and 2) Can physical activity above baseline result in sudden death among those individuals?
The experts conducted a multi-database search for English-language studies on SCT and pain crises or mortality, identifying 1474 such citations. Only seven of those studies reported original data, included laboratory testing for SCT in individuals, and addressed the two primary research questions.
Of these studies, none assessed acute pain crises in individuals with SCT compared to those with SCD and only one described death in individuals reported to have SCT. This study of active-duty U.S. soldiers found only that SCT was associated with a higher risk of heat-related-exertional rhabdomyolysis, or muscle breakdown, but not a higher risk of death from any cause. After the implementation of precautions to prevent heat and environmental-related injury in military personnel, the race-adjusted risk of death was no different in individuals with SCT compared to individuals without SCT.
“In the absence of two medical conditions that we are all at risk for, exertional rhabdomyolysis or crush injuries leading to rhabdomyolysis, individuals with SCT are not susceptible to sudden death. Even under these extreme environmental conditions, unexplained sudden death cannot be attributed to SCT,” said Dr. DeBaun. Taken together, these findings demonstrate that “in individuals with SCT, the likelihood of SCT alone or pain crises being the root cause of sudden death is medically impossible,” he added.
While conducting this systematic review, the experts found several studies in which the presence of sickled blood cells at autopsy was cited as evidence of death by acute pain crisis in individuals with SCT. However, the experts did not find any studies that had human data to support this hypothesis, nor any clinical descriptions sufficient to make a diagnosis of an acute pain crisis immediately preceding death.
“Medicine, even in the post-mortem setting, is science,” said corresponding study author Lachelle D. Weeks, MD, PhD, assistant professor of medicine at Harvard Medical School and physician-scientist in the division of population sciences at Dana-Farber Cancer Institute. “Our diagnoses have to make sense and be backed by medical evidence. Given the findings of this study, we owe it to individuals with SCT to ensure that post-mortem examinations check for evidence of rhabdomyolysis and other medical or traumatic causes of death.”
The review had some limitations, most notably a lack of high quality, peer-reviewed direct evidence. To help mitigate this challenge, panel members were encouraged to consider indirect evidence when reviewing abstracts and judged evidence certainty following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) framework. However, given this paucity of data, the experts hope this review prompts additional SCT research.
Following the results of this study, ASH revised its position statement on SCT, which states that listing “sickle cell crisis” or “sickle cell trait” as a cause of death on an autopsy report for an individual with sickle cell trait is medically inaccurate and without medical evidence of causation. To read the updated statement and learn more about ASH’s advocacy efforts in this area, visit https://hematology.org/advocacy.
In a paradigm shift in how we view mutations, researchers uncover forms of DNA damage in healthy cells – most particularly in blood stem cells – that can persist unrepaired for years.
While most known types of DNA damage are fixed by our cells’ in-house repair mechanisms, some forms of DNA damage evade repair and can persist for many years, new research shows. This means that the damage has multiple chances to generate harmful mutations, which can lead to cancer.
Scientists from the Wellcome Sanger Institute and their collaborators analysed family trees of hundreds of single cells from several individuals. The team pieced together these family trees from patterns of shared mutations between the cells, indicating common ancestors.
Researchers uncovered unexpected patterns of mutation inheritance in the trees, revealing that some DNA damage persists unrepaired. In the case of blood stem cells, this can be for two to three years.
The research, published in Nature, changes the way we think about mutations, and has implications for understanding the development of various cancers.
Throughout our life, all of the cells in our body accumulate genetic errors in the genome, known as somatic mutations. These can be caused by damaging environmental exposures, such as smoking, as well as the everyday chemistry occurring in our cells.
DNA damage is distinct from a mutation. While a mutation is one of the standard four DNA bases (A, G, T or C) in the wrong place, similar to a spelling mistake, DNA damage is chemical alteration of the DNA, like a smudged unrecognisable letter. DNA damage can result in the genetic sequence being misread and copied incorrectly during cell division, in a process known as DNA replication. This introduces permanent mutations that can contribute to the development of cancers. However, the DNA damage itself is usually recognised and mended quickly by repair mechanisms in our cells.
If researchers can better understand the causes and mechanisms of mutations, they may be able to intervene and slow or remove them.
In a new study, Sanger Institute scientists and their collaborators analysed data in the form of family trees of hundreds of single cells from individuals. The family trees are constructed from patterns of mutations across the genome that are shared between cells – for example, cells with many shared mutations have a recent common ancestor cell and are closely related.
The researchers collated seven published sets of these family trees, known as somatic phylogenies. The data set included 103 phylogenies from 89 individuals,1 spanning blood stem cells, bronchial epithelial cells and liver cells
The team found unexpected patterns of mutation inheritance in the family trees, revealing that some DNA damage can persist unrepaired through multiple rounds of cell division. This was particularly evident in blood stem cells, where between 15 to 20 per cent of the mutations resulted from a specific type of DNA damage that persists for two to three years on average, and in some cases longer.
This means that during cell division, each time the cell attempts to copy the damaged DNA it can make a different mistake, leading to multiple different mutations from a single source of DNA damage. Importantly, this creates multiple chances of harmful mutations that could contribute to cancer. Researchers suggest that although these types of DNA damage occur rarely, their persistence over years means they can cause as many mutations as more common DNA damage.
Overall, these findings change the way researchers think about mutations, and have implications for understanding the development of cancer.
Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, happen approximately twenty years before a clinical motor diagnosis in people with Huntington’s disease, finds a new study led by UCL researchers which appears in Nature Medicine.
The team found that although functions such as movement, thinking or behaviour remained normal for a long time before the onset of symptoms in Huntington’s disease, subtle changes to the brain were taking place up to two decades earlier. These findings pave the way for future preventative clinical trials, offer hope for earlier interventions that could preserve brain function and improve outcomes for individuals at risk of Huntington’s disease.
Huntington’s disease is a devastating neurodegenerative condition affecting movement, thinking and behaviour. It is a genetic disease and people with an affected parent have a 50% chance of inheriting the Huntington’s disease mutation, meaning they will develop disease symptoms – typically in mid-adulthood.
The disease is caused by repetitive expansions of three DNA blocks (C, A and G) in the huntingtin gene. This sequence tends to continually expand in certain cells over a person’s life, in a process known as somatic CAG expansion. This ongoing expansion accelerates neurodegeneration, making brain cells more vulnerable over time.
For the new study, the researchers studied 57 people with the Huntington’s disease gene expansion, who were calculated as being on average 23.2 years from a predicted clinical motor diagnosis.
They were examined at two time points over approximately five years to see how their bodies and brains changed over time. Their results were compared to 46 control participants, matched closely for age, sex and educational level.
As part of the study, all participants volunteered to undergo comprehensive assessments of their thinking, movement and behaviour, alongside brain scans and blood and spinal fluid sampling.
Importantly, the group with Huntington’s disease gene expansion showed no decline in any clinical function (thinking, movement or behaviour) during the study period, compared to the closely matched control group.
However, compared to the control group, subtle changes were detected in brain scans and spinal fluid biomarkers of those with Huntington’s disease gene expansion. This indicates that the neurodegenerative process begins long before symptoms are evident and before a clinical motor diagnosis.
Specifically, the researchers identified elevated levels of neurofilament light chain (NfL), a protein released into the spinal fluid when neurons are injured, and reduced levels of proenkephalin (PENK), a neuropeptide marker of healthy neuron state that could reflect changes in the brain’s response to neurodegeneration.
Lead author, Professor Sarah Tabrizi (UCL Huntington’s Disease Research Centre, UCL Queen Square Institute of Neurology, and UK Dementia Research Institute at UCL), said: “Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with the Huntington’s disease gene expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last five years mean we hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the next few years.”
The findings suggest that there is a treatment window, potentially decades before symptoms are present, where those at risk of developing Huntington’s disease are functioning normally despite having detectable measures of subtle, early neurodegeneration. Identifying these early markers of disease is essential for future clinical trials in order to determine whether a treatment is having any effect.
Co-first author of the study, Dr Rachael Scahill (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) said: “This unique cohort of individuals with the Huntington’s disease gene expansion and control participants provides us with unprecedented insights into the very earliest disease processes prior to the appearance of clinical symptoms, which has implications not only for Huntington’s disease but for other neurodegenerative conditions such as Alzheimer’s disease.”
This study is the first to establish a direct link between somatic CAG repeat expansion, measured in blood, and early brain changes in humans, decades before clinical motor diagnosis in Huntington’s disease.
While somatic CAG expansion was already known to accelerate neurodegeneration, this research demonstrates how it actively drives the earliest detectable changes in the brain: specifically in the caudate and putamen, regions critical to movement and thinking.
By showing that somatic CAG repeat expansion changes measured in blood predicts brain volume changes and other markers of neurodegeneration, the findings provide crucial evidence to support the hypothesis that somatic CAG expansion is a key driver of neurodegeneration.
With treatments aimed at suppressing somatic CAG repeat expansion currently in development, this work validates this mechanistic process as a promising therapeutic target and represents a critical advance towards future prevention trials in Huntington’s disease.
Co-first author of the study, Dr Mena Farag (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) added: “These findings are particularly timely as the Huntington’s disease therapeutic landscape expands and progresses toward preventive clinical trials.”
The research was done in collaboration with experts at the Universities of Glasgow, Gothenburg, Iowa, and Cambridge.
A little-noticed change to South Africa’s national health research guidelines, published in May of this year, has put the country on an ethical precipice. The newly added language appears to position the country as the first to explicitly permit the use of genome editing to create genetically modified children.
Heritable human genome editing has long been hotly contested, in large part because of its societal and eugenic implications. As experts on the global policy landscape who have observed the high stakes and ongoing controversies over this technology — one from an academic standpoint (Françoise Baylis) and one from public interest advocacy (Katie Hasson) — we find it surprising that South Africa plans to facilitate this type of research.
The fate of these three children, and whether they have experienced any negative long-term consequences from the embryonic genome editing, remains a closely guarded secret.
Controversial research
Considerable criticism followed the original birth announcement. Some argued that genetically modifying embryos to alter the traits of future children and generations should never be done.
Many pointed out that the rationale in this case was medically unconvincing – and indeed that safe reproductive procedures to avoid transmitting genetic diseases are already in widespread use, belying the justification typically given for heritable human genome editing. Others condemned his secretive approach, as well as the absence of any robust public consultation, considered a prerequisite for embarking on such a socially consequential path.
In the immediate aftermath of the 2018 revelation, the organizing committee of the Second International Summit on Human Genome Editing joined the global uproar with a statement condemning this research.
At the same time, however, the committee called for a “responsible translational pathway” toward clinical research. Safety thresholds and “additional criteria” would have to be met, including: “independent oversight, a compelling medical need, an absence of reasonable alternatives, a plan for long-term follow-up, and attention to societal effects.”
Notably, the additional criteria no longer included the earlier standard of “broad societal consensus.” https://www.youtube.com/embed/XAhFoaT6Kik?wmode=transparent&start=0 Nobel laureate David Baltimore, chair of the organizing committee for the Second International Summit on Human Genome Editing, talks about the importance of public global dialogue on gene editing.
New criteria
Now, it appears that South Africa has amended its Ethics in Health Research Guidelines to explicitly envisage research that would result in the birth of gene-edited babies.
Section 4.3.2 of the guidelines on “Heritable Human Genome Editing” includes a few brief and rather vague paragraphs enumerating the following criteria: (a) scientific and medical justification; (b) transparency and informed consent; (c) stringent ethical oversight; (d) ongoing ethical evaluation and adaptation; (e) safety and efficacy; (f) long-term monitoring; and (g) legal compliance.
While these criteria seem to be in line with those laid out in the 2018 summit statement, they are far less stringent than the frameworks put forth in subsequent reports. This includes, for example, the World Health Organization’s report Human Genome Editing: Framework for Governance (co-authored by Françoise Baylis).
Alignment with the law
Further, there is a significant problem with the seemingly permissive stance on heritable human genome editing entrenched in these research guidelines. The guidelines clearly require the research to comply with all laws governing heritable human genome research. Yet, the law and the research guidelines in South Africa are not aligned, which entails a significant inhibition on any possible research.
This is because of a stipulation in section 57(1) of the South African National Health Act 2004 on the “Prohibition of reproductive cloning of human beings.” This stipulates that a “person may not manipulate any genetic material, including genetic material of human gametes, zygotes, or embryos… for the purpose of the reproductive cloning of a human being.”
When this act came into force in 2004, it was not yet possible to genetically modify human embryos and so it’s not surprising there’s no specific reference to this technology. Yet the statutory language is clearly wide enough to encompass it. The objection to the manipulation of human genetic material is therefore clear, and imports a prohibition on heritable human genome editing.
Ethical concerns
Photo by Tingey Injury Law Firm on Unsplash
The question that concerns us is: why are South Africa’s ethical guidelines on research apparently pushing the envelope with heritable human genome editing?
In 2020, we published alongside our colleagues a global review of policies on research involving heritable human genome editing. At the time, we identified policy documents — legislation, regulations, guidelines, codes and international treaties — prohibiting heritable genome editing in more than 70 countries. We found no policy documents that explicitly permitted heritable human genome editing.
It’s easy to understand why some of South Africa’s ethicists might be disposed to clear the way for somatic human genome editing research. Recently, an effective treatment for sickle cell disease has been developed using genome editing technology. Many children die of this disease before the age of five and somatic genome editing — which does not involve the genetic modification of embryos — promises a cure.
Implications on future research
But that’s not what this is about. So, what is the interest in forging a path for research on heritable human genome editing, which involves the genetic modification of embryos and has implications for subsequent generations? And why the seemingly quiet modification of the guidelines?
How many people in South Africa are aware that they’ve just become the only country in the world with research guidelines that envisage accommodating a highly contested technology? Has careful attention been given to the myriad potential harms associated with this use of CRISPR technology, including harms to women, prospective parents, children, society and the gene pool?
Is it plausible that scientists from other countries, who are interested in this area of research, are patiently waiting in the wings to see whether the law in South Africa prohibiting the manipulation of human genetic material will be an insufficient impediment to creating genetically modified children? Should the research guidelines be amended to accord with the 2004 statutory prohibition?
Or if, instead, the law is brought into line with the guidelines, would the result be a wave of scientific tourism with labs moving to South Africa to take advantage of permissive research guidelines and laws?
We hope the questions we ask are alarmist, as now is the time to ask and answer these questions.
Katie Hasson, Associate Director at the Center for Genetics and Society, co-authored this article.
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
The CRISPR molecular scissors have the potential to revolutionise the treatment of genetic diseases. This is because they can be used to correct specific defective sections of the genome. Unfortunately, there is a catch: under certain conditions, the repair can lead to new genetic defects – as in the case of chronic granulomatous disease. This was reported in the journal Communications Biology by a team from the University of Zurich (UZH).
Chronic granulomatous disease is a rare hereditary disease that affects about one in 120 000 people. The disease impairs the immune system, making patients susceptible to serious and even life-threatening infections. It is caused by the absence of two letters, called bases, in the DNA sequence of the NCF1 gene. This error results in the inability to produce an enzyme complex that plays an important role in the immune defence against bacteria and moulds.
The CRISPR tool works…
The research team has now succeeded in using the CRISPR system to insert the missing letters in the right place. They performed the experiments in cell cultures of immune cells that had the same genetic defect as people with chronic granulomatous disease. “This is a promising result for the use of CRISPR technology to correct the mutation underlying this disease,” says team leader Janine Reichenbach, professor of somatic gene therapy at the University Children’s Hospital Zurich and the Institute for Regenerative Medicine at UZH.
… but unfortunately, it’s not perfect
Interestingly however, some of the repaired cells now showed new defects. Entire sections of the chromosome where the repair had taken place were missing. The reason for this is the special genetic constellation of the NCF1 gene: it is present three times on the same chromosome, once as an active gene and twice in the form of pseudogenes. These have the same sequence as the defective NCF1 and are not normally used to form the enzyme complex.
CRISPR’s molecular scissors cannot distinguish between the different versions of the gene and therefore occasionally cut the DNA strand at multiple locations on the chromosome – at the active NCF1 gene as well as at the pseudogenes. When the sections are subsequently rejoined, entire gene segments may be misaligned or missing. The medical consequences are unpredictable and, in the worst case, contribute to the development of leukaemia. “This calls for caution when using CRISPR technology in a clinical setting,” says Reichenbach.
Safer method sought
To minimise the risk, the team tested a number of alternative approaches, including modified versions of CRISPR components. They also looked at using protective elements that reduce the likelihood of the genetic scissors cutting the chromosome at multiple sites simultaneously. Unfortunately, none of these measures were able to completely prevent the unwanted side effects.
“This study highlights both the promising and challenging aspects of CRISPR-based therapies,” says co-author Martin Jinek, a professor at the UZH Department of Biochemistry. He says the study provides valuable insights for the development of gene-editing therapies for chronic granulomatous disease and other inherited disorders. “However, further technological advances are needed to make the method safer and more effective in the future.”
In a paper published in Nature Genetics, researchers are warning that artificial intelligence tools gaining popularity in the fields of genetics and medicine can lead to flawed conclusions about the connection between genes and physical characteristics, including risk factors for diseases like diabetes.
The faulty predictions are linked to researchers’ use of AI to assist genome-wide association studies, according to the University of Wisconsin–Madison researchers. Such studies scan through hundreds of thousands of genetic variations across many people to hunt for links between genes and physical traits. Of particular interest are possible connections between genetic variations and certain diseases.
Genetics’ link to disease not always straightforward
Genetics play a role in the development of many health conditions. While changes in some individual genes are directly connected to an increased risk for diseases like cystic fibrosis, the relationship between genetics and physical traits is often more complicated.
Genome-wide association studies have helped to untangle some of these complexities, often using large databases of individuals’ genetic profiles and health characteristics, such as the National Institutes of Health’s All of Us project and the UK Biobank. However, these databases are often missing data about health conditions that researchers are trying to study.
“Some characteristics are either very expensive or labour-intensive to measure, so you simply don’t have enough samples to make meaningful statistical conclusions about their association with genetics,” says Qiongshi Lu, an associate professor in the UW–Madison Department of Biostatistics and Medical Informatics and an expert on genome-wide association studies.
The risks of bridging data gaps with AI
Researchers are increasingly attempting to work around this problem by bridging data gaps with ever more sophisticated AI tools.
“It has become very popular in recent years to leverage advances in machine learning, so we now have these advanced machine-learning AI models that researchers use to predict complex traits and disease risks with even limited data,” Lu says.
Now, Lu and his colleagues have demonstrated the peril of relying on these models without also guarding against biases they may introduce. In their paper, they show that a common type of machine learning algorithm employed in genome-wide association studies can mistakenly link several genetic variations with an individual’s risk for developing Type 2 diabetes.
“The problem is if you trust the machine learning-predicted diabetes risk as the actual risk, you would think all those genetic variations are correlated with actual diabetes even though they aren’t,” says Lu.
These “false positives” are not limited to these specific variations and diabetes risk, Lu adds, but are a pervasive bias in AI-assisted studies.
New statistical method can reduce false positives
In addition to identifying the problem with overreliance on AI tools, Lu and his colleagues propose a statistical method that researchers can use to guarantee the reliability of their AI-assisted genome-wide association studies. The method helps remove bias that machine learning algorithms can introduce when they’re making inferences based on incomplete information.
“This new strategy is statistically optimal,” Lu says, noting that the team used it to better pinpoint genetic associations with individuals’ bone mineral density.
AI not the only problem with some genome-wide association studies
While the group’s proposed statistical method could help improve the accuracy of AI-assisted studies, Lu and his colleagues also recently identified problems with similar studies that fill data gaps with proxy information rather than algorithms.
In another recently published paper appearing in Nature Genetics, the researchers sound the alarm about studies that over-rely on proxy information in an attempt to establish connections between genetics and certain diseases.
For instance, large health databases like the UK Biobank have a ton of genetic information about large populations, but they don’t have very much data regarding the incidence of diseases that tend to crop up later in life, like most neurodegenerative diseases.
For Alzheimer’s disease specifically, some researchers have attempted to bridge that gap with proxy data gathered through family health history surveys, where individuals can report a parent’s Alzheimer’s diagnosis.
The UW–Madison team found that such proxy-information studies can produce “highly misleading genetic correlation” between Alzheimer’s risk and higher cognitive abilities.
“These days, genomic scientists routinely work with biobank datasets that have hundreds of thousands of individuals; however, as statistical power goes up, biases and the probability of errors are also amplified in these massive datasets,” says Lu. “Our group’s recent studies provide humbling examples and highlight the importance of statistical rigor in biobank-scale research studies.”
People with a rare genetic mutation that causes significant vision loss early in childhood experienced a 100-fold improvement in vision after receiving a corrective gene therapy. Some patients even experienced a 10 000-fold improvement in their vision after receiving the highest dose of the therapy, according to researchers from the Perelman School of Medicine at the University of Pennsylvania who co-led the clinical trial published in The Lancet.
“That 10 000-fold improvement is the same as a patient being able to see their surroundings on a moonlit night outdoors as opposed to requiring bright indoor lighting before treatment,” said the study’s lead author, Artur Cideciyan, PhD, a research professor of Ophthalmology and co-director of the Center for Hereditary Retinal Degenerations. “One patient reported for the first time being able to navigate at midnight outdoors only with the light of a bonfire.”
A total of 15 people participated in the Phase 1/2 trial, including three paediatric patients. Each patient had Leber congenital amaurosis as the result of mutations in the GUCY2D gene, which is essential to producing proteins critical for vision. This specific condition, which affects less than 100 000 people worldwideand is abbreviated as LCA1, causes significant amount of vision loss as early as infancy.
All subjects had severe vision loss with their best measure of vision being equal or worse than 20/80 – meaning if a typically-sighted person could see an object clearly at 80 feet (24m), these patients would have to move up to at least 20 feet (6m) to see it. Glasses provide limited benefit to these patients because they correct abnormalities in the optical focusing ability of the eye, and are unable to address medical causes of vision loss, such as genetic retinal diseases like LCA1.
The trial tested different dosage levels of the gene therapy, ATSN-101, which was adapted from the AAV5 microorganism and was surgically injected under the retina. For the first part of the study, cohorts of three adults each received either a low, mid, ore high dose. Evaluations were held between each level of dosage to ensure that they were safe before upping the dosage for the next cohort. A second phase of the study involved only administering the high dosage levels to both an adult cohort of three and a paediatric cohort of three, again after safety reviews of the previous cohorts.
Improvements were noticed quickly, often within the first month, after the therapy was applied and lasted for at least 12 months. Observations of participating patients are also ongoing. Three of six high-dosage patients who were tested to navigate a mobility course in varying levels of light achieved the maximum-possible score. Other tests used eye charts or measured the dimmest flashes of light patients perceived in a dark environment.
Of the nine patients who received the maximum dosage, two had the 10 000-fold improvement in vision.
“Even though we previously predicted a large vision improvement potential in LCA1, we did not know how receptive patients’ photoreceptors would be to treatment after decades of blindness,” said Cideciyan. “It is very satisfying to see a successful multi-center trial that shows gene therapy can be dramatically efficacious.”
Primarily, the study sought to determine the safety of the gene therapy and its varying dosage levels. Researchers did find some patients had side effects, but the overwhelming majority were related to the surgical procedure itself. The most common side effect was conjunctival haemorrhage, the breakage of small blood vessels underneath the clear surface of the eye, which healed. Two patients had eye inflammation that was reversed with a course of steroids. No serious side effects were related to the study drug.
This work comes on the heels of another successful ophthalmological trial at Penn restoring sight in patients with a different form of LCA. Earlier in 2024, CRISPR-Cas9 gene editing was used to improve the sight of many patients with a form of LCA tied to mutations in the CEP290 gene. Co-led by one of the new paper’s co-authors, Tomas S. Aleman, MD, professor in ophthalmology and co-director with Cideciyan of the Center for Hereditary Retinal Degenerations, the study used similar tests and was the first time children were involved in any gene editing work.
“The treatment success in our most recent clinical trials together with our earlier experience brings hope for a viable treatment for about 20 percent of infantile blindness caused by inherited retinal degenerations,” Aleman said. “The focus now is on perfecting the treatments and treating earlier manifestations of these conditions once safety is confirmed. We hope similar approaches will lead to equally positive outcomes in other forms of congenital retinal blindness.”
Moving forward, approval of this experimental medicine for clinical use requires a randomised controlled trial.
Sickle cell disease. Credit: National Institutes of Health
Individuals that have sickle cell trait, who did not which increases the risk of blood clots, a risk that is the same among diverse human populations that may not traditionally be associated with sickle cell disease. The study provides estimated clinical risks for people with sickle cell trait, which can inform clinical practice guidelines.
The study, published in Blood Advances, was led by researchers at National Human Genome Research Institute (NHGRI), part of NIH, The Johns Hopkins University School of Medicine, Baltimore, and the company 23andMe, South San Francisco, California. The researchers examined the largest and most diverse set of people with sickle cell trait to date, which includes data from over 19 000 people of various ancestral backgrounds with sickle cell trait.
While people with sickle cell trait typically do not have any associated health complications, they are carriers for sickle cell disease. In rare cases, sickle cell trait has been found to be a risk factor for health complications such as muscle breakdown, presence of blood in the urine and kidney disease.
Previous research investigating the relationship between sickle cell trait and blood clots have only included individuals of African genetic ancestry and self-identified Black participants because of the incorrect assumption that the genetic carrier state only affects those who identify as Black or African American. While sickle cell trait in the United States is most prevalent in individuals who self-identify as Black or African American, individuals from all ancestral backgrounds may have sickle cell trait. Sickle cell trait is often found in individuals living in or from West and Central Africa, Mediterranean Europe, India and the Middle East.
“Because sickle cell trait is often associated with people who identify as Black or African American, it is not widely studied in other populations, a bias that has led to unintended harm for those with sickle cell trait,” says Vence Bonham Jr, J.D., who co-led the study and serves as acting deputy director and associate investigator at NHGRI. “In particular, the racialisation of sickle cell trait has resulted in biased estimations of health risks. The results of our study will help clinicians properly contextualise the risk of blood clots amongst people with sickle cell trait without unintended bias.”
Individuals in this study are part of the 23andMe research program and have volunteered to participate in the research online and provided informed consent, which includes allowing their de-identified data to be analysed and subsequently shared with research collaborators. Using data from this research cohort, which consists of over four million participants, researchers calculated the risk of blood clots in the veins, also known as venous thromboembolism. Through statistical analyses, participants were grouped based on their genetic similarities into genetic ancestry groups. The study found that people with sickle cell trait have a 1.45-fold higher risk of venous thromboembolism than those without sickle cell trait, a risk that is similar across all studied genetic ancestry groups.
To help clinicians estimate the risk of blood clots in people with sickle cell trait in comparison to other genetic carrier states, the researchers analysed risk in people who are carriers for Factor V Leiden, a well-known inherited blood-clotting disorder. The study found that carriers for Factor V Leiden, which is more prevalent in people of European genetic ancestries, had an even higher risk of venous thromboembolism than people with sickle cell trait.
The researchers found that people with sickle cell trait have a higher risk of pulmonary embolism than those without sickle cell trait.
While previous studies have demonstrated that in individuals with sickle cell trait, the risk of blood clots occurring in the lungs is higher than the risk of clots occurring only in the legs, this study supports the link more definitively with a larger sample size.
“This study, therefore, provides important insights about patterns of venous blood clots and suggests a unique mechanism of blood clotting in people with sickle cell trait,” said Rakhi Naik, M.D., clinical director for the Division of Hematology at Johns Hopkins University, Baltimore, who co-led the study. “Knowing the risks of blood clots in people with sickle cell trait is important for situations such as surgeries or hospitalizations, which add to the risk of developing serious blood clots.”
Researchers from the Center for Healthy Aging, Department of Cellular and Molecular Medicine at the University of Copenhagen have made a breakthrough in lifespan research. They have discovered that a particular protein known as OSER1 has a great influence on longevity.
”We identified this protein that can extend longevity. It is a novel pro-longevity factor, and it is a protein that exists in various animals, such as fruit flies, nematodes, silkworms, and in humans,” says Professor Lene Juel Rasmussen, senior author behind the new study.
Because the protein is present in various animals, the researchers conclude that new results also apply to humans:
”We identified a protein commonly present in different animal models and humans. We screened the proteins and linked the data from the animals to the human cohort also used in the study. This allows us to understand whether it is translatable into humans or not,” says Zhiquan Li, who is a first author behind the new study and adds:
“If the gene only exists in animal models, it can be hard to translate to human health, which is why we, in the beginning, screened the potential longevity proteins that exist in many organisms, including humans. Because at the end of the day we are interested in identifying human longevity genes for possible interventions and drug discoveries.”
Paves the way for new treatment
The researchers discovered OSER1 when they studied a larger group of proteins regulated by the major transcription factor FOXO, known as a longevity regulatory hub.
“We found 10 genes that, when – we manipulated their expression – longevity changed. We decided to focus on one of these genes that affected longevity most, called the OSER1 gene,” says Zhiquan Li.
When a gene is associated with shorter a life span, the risk of premature aging and age-associated diseases increases. Therefore, knowledge of how OSER1 functions in the cells and preclinical animal models is vital to our overall knowledge of human aging and human health in general.
“We are currently focused on uncovering the role of OSER1 in humans, but the lack of existing literature presents a challenge, as very little has been published on this topic to date. This study is the first to demonstrate that OSER1 is a significant regulator of aging and longevity. In the future, we hope to provide insights into the specific age-related diseases and aging processes that OSER1 influences,” says Zhiquan Li.
The researchers also hope that the identification and characterization of OSER1 will provide new drug targets for age-related diseases such as metabolic diseases, cardiovascular and neuro degenerative diseases.
“Thus, the discovery of this new pro-longevity factor allows us to understand longevity in humans better,” says Zhiquan Li.
