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Using a new stem-cell based model made from skin cells, scientists found the first direct evidence that Stargardt-related ABCA4 gene mutations affect a layer of cells in the eye called the retinal pigment epithelium (RPE). The discovery points to a new understanding of Stargardt disease progression and suggests a therapeutic strategy for the disease, which currently lacks treatment. The study took place at the National Eye Institute (NEI), part of the National Institutes of Health. The findings published online today in Stem Cell Reports.
“This new model will accelerate development of therapies for Stargardt disease,” said NEI Director Michael F. Chiang, M.D. “We lack a therapy for this disease in part because it’s rare. This model theoretically creates an unlimited supply of human cells for study.” Stargardt affects about 1 in every 10,000 people in the U.S.
Stargardt disease causes progressive loss of central and night vision. The vision loss is associated with the toxic build-up of lipid-rich deposits in the RPE, whose main job is to support and nourish the retina’s light sensing photoreceptors. Under normal conditions, the ABCA4 gene makes a protein that prevents this toxic build-up. Prior research showed that Stargardt disease is caused by a variety of mutations in the ABCA4 gene. More than 800 ABCA4 mutations are known to be associated with a broad spectrum of Stargardt disease phenotypes.
One way the RPE supports photoreceptors is by ingesting their spent outer segments, which keeps the cell pruned and healthy. In Stargardt disease, many scientists believe that RPE cells die after they acquire toxic byproducts when they ingest outer segments, and that this in turn leads to photoreceptor death and vision loss.
Much of the current understanding of Stargardt disease was gained by studying mouse models, which are inherently limited owing to the wide genetic variability of the disease in humans. With a human model of RPE, the NEI investigators were able to determine if ABCA4 gene mutations directly affected the RPE independent of photoreceptors.
To develop the model, the researchers took skin cells from Stargardt patients, converted them to stem cells, and then coaxed the stem cells to differentiate into RPE cells. Examining the patient-derived RPE, researchers detected ABCA4 protein on the RPE cell membrane. They explored the function of ABCA4 in RPE development by using the gene editing technology CRISPR/Cas9 to generate patient-derived RPE lacking ABCA4, called an ABCA4 knockout. They found that loss of ABCA4 did not affect maturation of the patient-derived RPE.
However, when the RPE lacking ABCA4 were exposed to normal (wild type) photoreceptor outer segments, the RPE cells accumulated intracellular lipids deposits.
Further tests of the ABCA4 knockouts showed evidence of defective RPE lipid metabolism and an impaired ability to digest photoreceptor outer segments, leading to lipid deposits in RPE cells.
This is the first report where loss of ABCA4 function in human RPE has been associated with intracellular lipid deposits in those cells, without exposure to ABCA4 mutant photoreceptor outer segments. Over time, these lipid deposits may contribute to RPE atrophy, leading to photoreceptor degeneration.
“Our report provides guidance for a gene therapy approach to target RPE,” said the study’s lead investigator, Kapil Bharti, Ph.D., senior investigator of the NEI Ocular and Stem Cell Translational Research Section. “Our data suggests that in addition to correcting ABCA4 loss of function in photoreceptors, gene therapies need to also target RPE cells.”
This research is part of a larger effort by the NEI to address the limited availability of patient-derived stem cell lines for studying Stargardt disease. To overcome this barrier, the NEI initiated a STGD1-iPSC banking program from patients with different ABAC4 mutations. These cells will be made available to the community at-large for mechanistic and genotype-phenotype studies.
The work was funded by the NEI Intramural Research Program.
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Materials provided by NIH/National Eye Institute. Note: Content may be edited for style and length.

Colorectal cancer is one of the most common cancers. Its treatment is mainly based on chemotherapy. However, over time, chemotherapy induces resistance in the majority of patients, who end up being unresponsive to the drugs. As a result, the five-year survival rate for those affected is still low. After succeeding in reproducing this resistance in the laboratory, a team from the University of Geneva (UNIGE) has found a way to overcome it. The team has used an optimized combination of drugs belonging to the class of tyrosine kinase inhibitors, which take different pathways to attack cancer cells than chemotherapy. These results, to be found in the journal Cancers, open up new avenues for overcoming treatment resistance and for developing new therapies that are more targeted than chemotherapy.
Colorectal cancer is the third most diagnosed cancer in the world and second only to lung cancer in terms of mortality. It most often develops from the age of 50 in the terminal part of the colon. It results from a change in the DNA of certain cells present in this organ. These cells become cancerous and proliferate in an uncontrolled manner until they form a primary tumour. As in many cancers, these cells can migrate to other parts of the body and form secondary tumours. This is known as metastatic cancer.
While genetics play a role in the development of the disease, the presence of inflammatory bowel diseases (e.g. Crohn’s disease) and certain dietary habits (alcohol, red meat) are also risk factors. In the case of a primary tumour, treatment is based on surgery and chemotherapy. In the case of secondary tumours, it is based on a combination of chemotherapies. These treatments are non-targeted and aggressive. They cause significant side effects. They also lead to progressive resistance to treatment in majority of patients.
The phenomenon reproduced in the laboratory
A UNIGE team led by Patrycja Nowak-Sliwinska, an associate professor in the School of Pharmaceutical Sciences at the Faculty of Science of the UNIGE, has succeeded in studying precisely this resistance phenomenon in cancer cells. The team has also discovered a way to overcome it by using a combination of tyrosine kinase inhibitors. Tyrosine kinases allow the transport of a phosphate group to a key protein for cell division and growth. With a specific mixture of inhibitor molecules, these enzymes are ”blocked” and this transport is interrupted. The proliferation of tumour cells is then stopped or slowed down.
To make this discovery, the UNIGE team used cancer cell lines from different patients. After letting these cells proliferate in the laboratory, they exposed them chronically to FOLFOXIRI, the most common chemotherapy combination for treating colorectal cancer. ”After about 34 to 50 weeks of exposure, we managed to obtain in vitro this phenomenon of acquired chemoresistance, as we observe in a clinical situation”, explains Patrycja Nowak-Sliwinska, the last author of the study.
Taking an alternative path
The scientists then noted that the resistant cells showed a desensitization of the plasma membrane, i.e. their envelope, which had become less permeable to the molecules coming from the chemotherapeutic products. They therefore do not penetrate or no longer penetrate sufficiently inside these cells. Still within this membrane, the researchers observed a deregulation of certain genes responsible for the lipid circulation networks, which must be specified.
”We then exposed the resistant cells to a combination of tyrosine kinase inhibitors previously optimized in our laboratory. We noticed that they made it possible to overcome this resistance by taking another ‘path’ than the one used by the chemotherapy molecules to signal the cell,” says George M. Ramzy, a PhD student in the School of Pharmaceutical Sciences at the Faculty of Science of the UNIGE and first author of the study.
The research team succeeded in blocking up to 82% of the metabolic activity of these cells — i.e. their energy supply — and thus considerably weakening them. This discovery opens up new avenues for overcoming the phenomenon of resistance in colorectal cancer, which is responsible for the low five-year survival rate of patients. ”In addition to overcoming resistance, this treatment has the advantage of acting in a targeted manner. Its action is specific to tumour cells, which is not the case with chemotherapies, which act aggressively on a broader spectrum of cells,” concludes Patrycja Nowak-Sliwinska.
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Rates of one type of stroke called subarachnoid hemorrhage have increased in older people and men in recent years, and such strokes occur in Black people at a disproportionately higher rate compared to people of other races and ethnicities, according to a study published in the October 26, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology.
A subarachnoid hemorrhage is when bleeding occurs, usually from a burst blood vessel, in the space between the brain and the membrane that covers it. This type of stroke can be caused by a rupture of an aneurysm, high blood pressure or trauma. For this study, researchers looked only at those not caused by trauma.
“Subarachnoid hemorrhages unrelated to trauma account for 5% to 10% of all strokes in the United States, and are often deadly,” said study author Fadar Oliver Otite, M.D., Sc.M., of the SUNY Upstate Medical University in Syracuse, N.Y. “Not only did we find an increase in these strokes over recent years, we also found the incidence was disproportionally higher and increasing in Black people while rates did not increase in people of other races and ethnicities.”
For the study, researchers reviewed state hospitalization databases for New York and Florida and identified 39,475 people hospitalized for non-traumatic subarachnoid hemorrhage between 2007 and 2017. Using Census data, they then calculated the annual rates of this type of stroke in those states and compared those rates over time for men, women, various age ranges, races and ethnicities.
Researchers found that over the 10-year study, the average incidence of this type of stroke for all participants was 11 cases per 100,000 people. Rates were higher in women with 13 cases per 100,000 people, and lower in men with 10 cases. Incidence also increased with age. For middle-aged men, the average was four cases per 100,000 people while for men 65 and older, the average was 22 cases. Incidence increased over time, by 0.7% on average per year overall, with most of the increase in middle-aged men at 1.1%, older men at 2.3% and older women at 0.7%, while the incidence in young women declined by 0.7%.
When looking at race and ethnicity, researchers found incidence was greater in Black people with an average of 15 cases per 100,000 people compared to non-Hispanic white people with an average of 10 cases.
Incidence increased in Black people by 1.8% per year while rates for Hispanic, Asian and non-Hispanic white people did not change over time.
“The incidence of this type of stroke is disproportionately higher, and increasing, in Black people, leading to a widening of the racial incidence gap,” said Otite. “Previous studies have found Black people develop high blood pressure younger and are more likely to have uncontrolled high blood pressure than non-Hispanic white people, so expanding efforts to control blood pressure may help reduce rates.The causes also likely extend to socioeconomic factors including structural racism. Tackling racial disparities will require multifaceted interventions targeted at stroke risk factors and socioeconomic inequity.”
A limitation of the study was researchers were unable to differentiate between strokes caused by aneurysms and those not caused by aneurysms, which would have provided further insight.
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“Monkeypox and H.I.V. have collided,” a C.D.C. researcher said.Nearly all Americans hospitalized for monkeypox infection had weakened immune systems, most often because of H.I.V. infection, the Centers for Disease Control and Prevention reported on Wednesday.Of 57 hospitalized patients described in the report, 82 percent had H.I.V. More than two-thirds of the patients were Black and nearly one-quarter were homeless, reflecting racial and economic inequities seen in the outbreak overall.The finding suggests that although most cases of monkeypox are mild, doctors should test patients with suspected cases for H.I.V. as well, and be prepared to offer prompt treatment for both infections.“Monkeypox and H.I.V. have collided with tragic effects,” Dr. Jonathan Mermin, the C.D.C.’s lead scientist on monkeypox, said in a statement.Most of the patients in the study were given tecovirimat, or Tpoxx, but treatment for some patients was delayed by as long as four weeks after they first sought care.As of Tuesday, more than 28,000 cases of monkeypox had been reported in the United States, and nearly 76,000 cases worldwide. A vast majority are still among men who have sex with men, according to the C.D.C.The number of new monkeypox infections has declined steadily since September. But the number of high-risk people opting for vaccination has also dropped. Only 7 percent of the vaccine doses administered so far have gone to recipients who are Black.People living with H.I.V. or with other conditions that weaken the immune system fared poorly in previous outbreaks of monkeypox in African countries.In the new report, C.D.C. scientists analyzed case reports from 57 patients older than 18 who were hospitalized for monkeypox between Aug. 10 and Oct. 10. Roughly 95 percent of the patients were male.All of them had skin rashes, and most also had severe lesions in the mouth, urethra, rectum or vagina. About one in five experienced symptoms in their lungs and eyes, and in four patients the brain and spinal cord were affected.Four of the 47 patients with H.I.V. were taking drugs to suppress the virus before they were diagnosed with monkeypox. About one in three had a CD4 count — a proxy for the immune system’s strength — of less than 50, indicating severe immunosuppression.Two of the patients, one of whom had H.I.V., were being treated for cancer; three were solid organ transplant recipients; and three were pregnant. All of these conditions are linked to a weakened immune system.One third of the patients were admitted to intensive care units. Of the 12 recorded deaths, five were a result of complications from monkeypox infection, six are under investigation and one was determined to be unrelated.

Published9 hours agoSharecloseShare pageCopy linkAbout sharingImage source, Phospho Biomedical AnimationScientists have discovered more about the mysterious role of epigenetics, the study of how genes change, in controlling the way cancers develop.Often called “dark matter”, it could alter the way cancer is detected and treated, research from The Institute of Cancer Research suggests.And it could lead to new forms of tests for the disease which would help tailor treatments.But this is a long way off, with research still at an early stage.When most people think of genetics, they think of structural changes to the DNA code that are passed down the generations.As a result, there has been huge focus on how these gene mutations drive the growth of cancers.But, in recent years, scientists have discovered another phenomenon which is not quite so straightforward, called epigenetics.Epigenetics is the study of how an individual’s behaviour and environment can cause changes that affect the way their genes work.Your epigenetics change as you age, and in response to where you live and how you live.Epigenetics does not alter the DNA code, but it can control access to genes, and is increasingly seen as playing an important role in the development of cancer.What is epigenetics? Prof Trevor Graham, director of the Centre for Evolution and Cancer at The Institute of Cancer Research in London, said: “We’ve unveiled an extra level of control for how cancers behave – something we liken to cancer’s ‘dark matter’.”He told the BBC that there can be “tangles in lines of DNA” as they fold up in each cell and this can change which genes are read.The position of the tangles can be very important in determining how cancers behave, he added.”It’s not going to change clinical care tomorrow but could be an avenue for developing new therapies,” Prof Graham said.Genetic testing for cancer mutations, such as BRCA which increases the risk of breast cancer, for example, only offers part of the picture about someone’s cancer.”By testing for both genetic and epigenetic changes, we could, potentially, much more accurately predict which treatments will work best for a particular person’s cancer,” Prof Graham said.The findings are published in two papers in Nature – the first analysed more than 1,300 samples from 30 bowel cancers, showing that epigenetic changes were very common in cancerous cells and helped them grow more than other cells.The second paper looked at lots of samples taken from different parts of the same tumour. It found that the way cancer cells develop is often governed by factors other than DNA mutations.The researchers say their findings cannot prove that epigenetic changes directly lead to alterations in the way cancers behave, and more work needs to be done to show this occurs.More on this storyHealth Explained: Epigenetics14 March 2012Related Internet LinksThe Institute of Cancer Research, LondonThe BBC is not responsible for the content of external sites.

Published8 hours agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesBy Evelyne MusambiBBC News, NairobiWhen Susan Wamaitha started feeling sick a year ago, she thought it was the side effects of a contraceptive pill she had started taking a few months earlier – but it turned out that she was eight weeks pregnant.The 32 year old is now a mother of three children. Unbeknown to her, the pill that she began using in June 2021 was banned in Kenya.Its street name in Kenya is “Sofia” but it is manufactured in China and all the details about the product on the packaging are only written in Chinese.A translation of the first line says it contains “Levonorgestrel Fast Estradiol Tablets”. The pill is a “long-acting oral contraceptive”, according to the second line. Then there is information about the manufacturer on the third: “Zizhu Pharmaceutical Co Ltd”.The sale of the pill was prohibited by Kenya’s authorities 10 years ago because of high levels of levonorgestrel – more than 40 times the recommended levels.Levonorgestrel is a hormonal medication used in a number of birth control methods.The health ministry did not share the full lab results about its findings, but said children conceived after the pill failed were found to have developed early puberty.Headaches and nausea”I did not know it was banned. Many of my friends were using it and had no side effects,” Ms Wamaitha told the BBC.Like many other Kenyan women, she was attracted to the pill by its affordability and the convenience of taking it only once a month.Image source, PPBWomen tend to buy the Sofia tablet each month – most suppliers will not sell it in bulk. Each pill costs between 300 Kenyan shillings ($2.50; £2.20) and 400 Kenyan shillings.Other family planning methods available in the country include the daily contraceptive pill. A month’s supply costs about $1.70 from government hospitals but their stock is not always guaranteed so women then have to buy it from pharmacies for considerably more.This makes the hormonal implant that lasts three months, offered at state clinics at a cost of around $5, and various intrauterine devices, like coils, that last several years and cost up to $9, more common alternatives.Condoms are offered for free in public offices and toilets but sometimes run out, though they can be bought in shops.”Because I had a non-hormonal copper T-shaped coil that was giving me back pains, I decided to remove it and use the pill,” Ms Wamaitha told the BBC. She was also impressed that her friends who recommended Sofia had not gained any weight – a key consideration for her as she says she struggles with keeping the pounds off.However, right from the beginning she did not feel great on it – though she thought it would just take time for her body to get used to the new medication as she had to take two pills initially followed by one a month.”I started having headaches and nausea. The first month I missed my period,” Ms Wamaitha said.But she did not worry as she had her period the following month. It was only when it skipped again in the third month that she began to get concerned.Her husband then started researching the contraceptive pill and that is when he found out it had been banned.”We started panicking about using a banned pill and when I realised I was pregnant I was worried about the effects it may have on my baby,” she said.They now have a healthy three-month-old girl, but the couple are upset by the lack of information and possible implications for their daughter as she grows up.’One size does not fit all’Only 50% of women in sub-Saharan Africa in need of modern contraceptive methods have access to them, according to the World Health Organization (WHO).Josephine KibaruA woman is likely to trust a neighbour and friend more than a healthcare worker who has been posted at the dispensary”Dr Josephine KibaruPopulation and development expertIn Kenya, contraception tends to be discussed in hushed tones – mostly because of cultural and religious beliefs in what is a patriarchal society.Some men do not allow their wives to use contraceptives while some religious sects are against it. The Kavonokya Sect in eastern Kenya, for example, rejects all modern medicine as it believes the Bible only recommends prayer as an intervention.For population and development expert Dr Josephine Kibaru, a grassroots approach would be best to gain acceptance for modern family planning methods.”We need community health volunteers to be more empowered with information because a woman is likely to trust a neighbour and friend more than a healthcare worker who has been posted at the dispensary,” Dr Kibaru told the BBC.She says there is a chasm of ignorance about the birth control methods available, along with many myths and misconceptions that need to be dispelled. A combination of both is probably what is required as gynaecologist Brigid Monda says women should consult healthcare providers to be able to find a family planning method that works for them.”One size does not fit all,” she told the BBC.Yet some women have also been forced to mix different contraceptive methods because of a lack of consistent supply at dispensaries located in rural areas.Sofia remains easily available despite its ban. The fact that women do not know it is banned is down to poor public health messaging, according to Dr Kibaru.”Using the media alone is not enough. Intentional public messaging at grassroots level is important to ensure the masses understand well why a drug has been banned,” she says.Sold to trusted customersPharmacists do know it is banned – another warning was issued by the health ministry last month – yet they still sell the pill because of demand. It is not on display, but sold under the counter to trusted customers who come in to buy it each month.The BBC visited several pharmacies in the capital, Nairobi, to make inquiries about Sofia – most said the drug was not for sale.One seller – who spoke on condition of anonymity – explained that it was available, just not on display, and pharmacies were able to buy it from suppliers who brought it in from neighbouring countries.Earlier this month, a Pharmacy and Poisons Board (PPB) official told Kenya’s Standard newspaper a shipment had been intercepted at the Ugandan border. Ms Wamaitha says she actually bought her pills from a friend who gets them in bulk from one of these suppliers.She says this friend and others knew the pill was banned when they recommended it to her.Her pregnancy has not persuaded them to stop using it – nor do any of the complaints on the various Facebook groups for Kenyan mothers.On at least three of these forums there have been discussions about Sofia, where several women taking it said they had fallen pregnant.This has convinced Ms Wamaitha to keep on urging her friends and other women to consider a different form of birth control.”I just know that the mention of that Sofia pill makes me get chills on my body. I don’t know what family planning method I will use to prevent a fourth pregnancy, but I’m done, done with that pill.”You may also be interested in:Kenyan mothers choose between work and their babies’My mother died without telling me I had HIV’This video can not be playedTo play this video you need to enable JavaScript in your browser.Around the BBCAfrica Today podcasts

Researchers at the University of Colorado School of Medicine have discovered that a unique bacteria found in the gut could be responsible for triggering rheumatoid arthritis (RA) in people already at risk for the autoimmune disease.
Kristine Kuhn, MD, PhD, associate professor of rheumatology, led a team of researchers from the Division of Rheumatology on the study, which published on October 26 in the journal Science Translational Medicine. CU School of Medicine student Meagan Chriswell is the lead author of the paper.
“Work led by co-authors Drs. Kevin Deane, Kristen Demoruelle, and Mike Holers here at CU helped establish that we can identify people who are at risk for RA based on serologic markers, and that these markers can be present in the blood for many years before diagnosis,” Kuhn says. “When they looked at those antibodies, one is the normal class of antibody we normally see in circulation, but the other is an antibody that we usually associate with our mucosa, whether it be the oral mucosa, the gut mucosa, or the lung mucosa. We started to wonder, ‘Could there be something at a mucosal barrier site that could be driving RA?'”
Discovering a new bacterium
The CU researchers, with the help of a group led by Bill Robinson, MD, PhD, at Stanford University, took the antibodies created by immune cells from individuals whose blood markers showed they were at risk for the disease and mixed them with the feces of the at-risk individuals to find the bacteria that were tagged by the antibodies.
To further test their hypothesis, the researchers used animal models to host the newly discovered bacteria. Those experiments showed that not only did the bacteria cause the animal models to develop the blood markers found in individuals at risk for RA; but some of the models showed development of full-blown RA as well.

Two new studies from Washington University School of Medicine in St. Louis support development of a broadly applicable treatment for neurodegenerative diseases that targets a molecule that serves as the central executioner in the death of axons, the wiring of the nervous system.
Blocking this molecular executioner prevents axon loss, which has been implicated in many neurodegenerative diseases, from peripheral neuropathies to Parkinson’s disease, and glaucoma to amyotrophic lateral sclerosis (ALS).
The new studies, both published Oct. 26 in the Journal of Clinical Investigation, reveal surprising details about how the molecule — called SARM1 — triggers axon death that underlies the development of neurodegenerative diseases. The research also points to new therapeutic approaches for diseases defined by axon loss.
“We desperately need treatments for neurodegenerative diseases,” said co-senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “With the evidence of SARM1’s central role in these diseases, we’re very interested in finding ways to block this molecule — whether with small molecule inhibitors or gene therapy techniques. Our latest research suggests we also may be able to interfere with its ability to drive damaging neuroinflammation. We’re hopeful this work will lead to effective new therapies across a range of neurodegenerative and neuroinflammatory diseases.”
In 2017, Milbrandt and co-senior author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, discovered that SARM1 is an enzyme that can promote neurodegeneration. Soon after, they co-founded a startup company called Disarm Therapeutics to boost the development of drug compounds that inhibit SARM1 for the treatment of diseases characterized by axon degeneration. In 2020, Disarm Therapeutics was acquired by Eli Lilly and Company to further the development of SARM1-targeted therapies for neurodegenerative diseases.
In healthy neurons, SARM1 is always switched off. But after injury or due to disease, SARM1 becomes active. Activated SARM1 is an arsonist — burning so much cellular energy that the axons can’t survive. This energy crisis triggers axons to disintegrate.
To understand more about SARM1’s role in triggering axon destruction, the researchers studied a mysterious and extremely rare progressive neuropathy syndrome — so rare, it lacks a name. This rare disease turned out to be a good model for understanding the role of the immune system in neuroinflammatory conditions generally. Sequencing patient genomes, the researchers found that the axon loss was caused by genetic errors in the gene NMNAT2, whose normal function keeps SARM1 turned off. Due to these genetic errors, SARM1 is constantly activated, which triggers axon destruction. The researchers used the CRISPR gene-editing technique to reproduce these mutations in mice. Like people with the syndrome, these mice survived to adulthood but had worsening motor dysfunction, loss of peripheral axons and, importantly, an infiltration of immune cells called macrophages.
The researchers were surprised to find that reducing the number of macrophages reversed the axon loss and disease symptoms in the mice. The study suggests that SARM1 not only contributes directly to axon loss but also plays a role in driving neuroinflammation that only serves to compound the problems. The findings also suggest that some neurodegenerative conditions could be treated with immune modulating drugs that block macrophages or other inflammatory immune cells.
In the second paper, the researchers investigated the possible role of SARM1 in Charcot-Marie-Tooth disease type 2a, a common form of inherited peripheral neuropathy and a good model to study axon loss generally. Patients with this disease have progressive loss of motor and sensory axons and develop difficulty walking, muscle weakness, and tingling or burning sensations in the hands and feet. The disease is caused by a mutation in an important protein in mitochondria, the energy factories of cells. The mutation, in a protein called mitofusin2, impairs the normal function of mitochondria. Much research has focused on the abnormal mitochondria, assuming they must be the root of the problem in this disease.
Surprisingly, the researchers found that deleting SARM1 in a rodent model of Charcot-Marie-Tooth disease type 2a stopped most of the problems the animals exhibited — independent of the diseased mitochondria. Eliminating SARM1 blocked or slowed axon death, muscle atrophy, mitochondrial abnormalities and problems with neuromuscular junctions, where the neurons interface with muscle. Even with the mutant mitofusin2 protein present, deleting SARM1 protected the mitochondria from further degradation and dysfunction.
“When we block SARM1, we not only protect the axons, we get much healthier mitochondria,” DiAntonio said. “This was a complete surprise, but we are hopeful it could be relevant in many neurodegenerative diseases where mitochondrial damage is central, such as Parkinson’s disease, as many neurodegenerative diseases have a component of mitochondrial dysfunction.”
Milbrandt and DiAntonio are co-founders, scientific advisory board members and shareholders of Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly and Company. Disarm Therapeutics and Eli Lilly are developing SARM1-targeted therapies for neurodegenerative diseases.

Researchers at Oregon State University and Oregon Health & Science University have taken a key step toward improving and lengthening the lives of cystic fibrosis patients, who experience chronically clogged airways and a dramatically shortened life expectancy.
The team of scientists and clinicians has engineered inhalable lipid nanoparticles that can effectively deliver messenger RNA to the lungs, prompting lung cells to manufacture the protein that thwarts the disease.
Findings were published in ACS Nano.
The research was led by postdoctoral scholar Jeonghwan Kim and Gaurav Sahay, an associate professor of pharmaceutical sciences in the OSU College of Pharmacy who studies lipid nanoparticles, or LNPs, as a gene delivery vehicle with a focus on cystic fibrosis. Lipids are fatty acids and similar organic compounds including many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter.
Cystic fibrosis is a progressive genetic disorder that results in persistent lung infection and affects 30,000 people in the U.S., with about 1,000 new cases identified every year. More than three-quarters of patients are diagnosed by age 2, and despite steady advances in alleviating complications, the median life expectancy is still just 40 years.
One faulty gene — the cystic fibrosis transmembrane conductance regulator, or CFTR — causes the disease, which is characterized by lung dehydration and mucous buildup that blocks the airway.

The debate performance on Tuesday night by Lt. Gov. John Fetterman, the Democratic nominee for Senate in Pennsylvania, left party officials newly anxious, injecting a fresh dose of unpredictability into one of the country’s most important contests less than two weeks before Election Day.Five months after surviving a serious stroke, Mr. Fetterman cut a sharp contrast with Mehmet Oz, a quick-spoken former talk show host, as he haltingly provided answers to questions using closed captioning to accommodate the auditory processing impairments he has been confronting. At times, Mr. Fetterman seemed to pause to seek the right words or offered a jumble of sentences to express his positions. In some cases, he contradicted himself or appeared to state the opposite of his actual view.The contentious matchup between Mr. Fetterman and Dr. Oz, his Republican rival, was a kind of political duel rarely seen in American life, upending the traditional pageantry of rapid-fire debates.Mr. Fetterman’s performance thrust questions about health and disability into the center of the final weeks of a nearly deadlocked race. Even as doctors and disability rights advocates praised his delivery, saying that his speech did not reflect any cognitive impairment and that he had offered an inspiring model for others with disabilities, some Democrats worried that ordinary voters might see it differently.“I was nervous before the debate began, and I’m still nervous,” said Ed Rendell, a Democratic former governor of Pennsylvania, who added that the format — with 60-second answers and 15- and 30-second rebuttals — made it more difficult for Mr. Fetterman to respond fluidly. “You never know which way this goes.”One senior Democratic official in the state described an intense level of anxiety, and an awareness that the debate could be decisive.Republicans clearly saw an opening.“Fetterman proved he’s incapable of the physical and communication demands of the job,” said former Representative Ryan Costello, a Republican from the Philadelphia suburbs who also criticized Mr. Fetterman over issues of transparency.“This is a six-year term,” he said. “This is a serious job.”The outcome of the contest could decide control of the Senate — determining whether President Biden will be able to keep confirming federal judges, and whether he will confront investigations and conservative legislation from both chambers of Congress or only from what is widely expected to be a Republican-controlled House.For many voters, the verdict on Mr. Fetterman will be decided in the days to come. Few voters watch entire debates, leaving most to learn about what happened through videos that circulate in the days and weeks that follow.Democratic officials and campaign operatives in Pennsylvania quickly seized on a statement by Dr. Oz that abortion decisions should be up to “women, doctors, local political leaders.” Those involved with the Fetterman campaign said they had made the right decision in going forward with the debate, arguing that it had given them a politically damaging moment for Dr. Oz that would linger longer than Mr. Fetterman’s overall performance.The State of the 2022 Midterm ElectionsElection Day is Tuesday, Nov. 8.Bracing for a Red Wave: Republicans were already favored to flip the House. Now they are looking to run up the score by vying for seats in deep-blue states.Pennsylvania Senate Race: Lt. Gov. John Fetterman and Mehmet Oz clashed in one of the most closely watched debates of the midterm campaign. Here are five takeaways.Polling Analysis: If these poll results keep up, everything from a Democratic hold in the Senate and a narrow House majority to a total G.O.P. rout becomes imaginable, writes Nate Cohn, The Times’s chief political analyst.Strategy Change: In the final stretch before the elections, some Democrats are pushing for a new message that acknowledges the economic uncertainty troubling the electorate.On Wednesday, the Fetterman team turned Dr. Oz’s remark into an ad for television and digital platforms and blasted it across social media.“I want women, doctors, local political leaders — letting the democracy that’s always allowed our nation to thrive — to put the best ideas forward so states can decide,” Dr. Oz said on Tuesday, after repeatedly declining to say directly whether he would support a 15-week federal ban on abortion.The comment, Fetterman allies said, allows Democrats to tie Dr. Oz to Doug Mastriano, the struggling Republican nominee for governor, who has vowed to ban abortion without exceptions. Mr. Fetterman’s campaign said it had raised $2 million since the debate, a number it said illustrated the steadfast commitment of the party’s base.“John obviously struggled with some words,” said Mike Mikus, a Democratic strategist in Pennsylvania. “I thought he would have performed better. But in the end, mashing up some words is not going to matter to swing voters.”Republicans, looking to capitalize on the debate, highlighted a moment when Mr. Fetterman was questioned on his views on fracking. In a 2018 interview, he expressed opposition to it; he now says that he has “always” supported the practice — a major issue in the state. But it was also a moment that showed Mr. Fetterman’s difficulties with articulating his thoughts. Mr. Fetterman said the captions did not make clear that the question was directed to him, causing him to pause before answering, according to a senior campaign aide.When pressed on his previous opposition, Mr. Fetterman paused and said: “I do support fracking and, I don’t, I don’t — I support fracking and I stand — I do support fracking.”Lt. Gov. John Fetterman of Pennsylvania last week.Haiyun Jiang/The New York TimesEarlier in the race, the Oz campaign mocked Mr. Fetterman repeatedly over his health. But at a campaign event on Wednesday in Harrisburg, Pa., as he appeared with Nikki R. Haley, the former United Nations ambassador, Dr. Oz sought to keep his focus firmly on matters of public safety, in keeping with Republican efforts to tar Mr. Fetterman as radically anti-law enforcement, a message he has vehemently rejected..css-1v2n82w{max-width:600px;width:calc(100% – 40px);margin-top:20px;margin-bottom:25px;height:auto;margin-left:auto;margin-right:auto;font-family:nyt-franklin;color:var(–color-content-secondary,#363636);}@media only screen and (max-width:480px){.css-1v2n82w{margin-left:20px;margin-right:20px;}}@media only screen and (min-width:1024px){.css-1v2n82w{width:600px;}}.css-161d8zr{width:40px;margin-bottom:18px;text-align:left;margin-left:0;color:var(–color-content-primary,#121212);border:1px solid var(–color-content-primary,#121212);}@media only screen and (max-width:480px){.css-161d8zr{width:30px;margin-bottom:15px;}}.css-tjtq43{line-height:25px;}@media only screen and (max-width:480px){.css-tjtq43{line-height:24px;}}.css-x1k33h{font-family:nyt-cheltenham;font-size:19px;font-weight:700;line-height:25px;}.css-1hvpcve{font-size:17px;font-weight:300;line-height:25px;}.css-1hvpcve em{font-style:italic;}.css-1hvpcve strong{font-weight:bold;}.css-1hvpcve a{font-weight:500;color:var(–color-content-secondary,#363636);}.css-1c013uz{margin-top:18px;margin-bottom:22px;}@media only screen and (max-width:480px){.css-1c013uz{font-size:14px;margin-top:15px;margin-bottom:20px;}}.css-1c013uz a{color:var(–color-signal-editorial,#326891);-webkit-text-decoration:underline;text-decoration:underline;font-weight:500;font-size:16px;}@media only screen and (max-width:480px){.css-1c013uz a{font-size:13px;}}.css-1c013uz a:hover{-webkit-text-decoration:none;text-decoration:none;}How Times reporters cover politics. We rely on our journalists to be independent observers. So while Times staff members may vote, they are not allowed to endorse or campaign for candidates or political causes. This includes participating in marches or rallies in support of a movement or giving money to, or raising money for, any political candidate or election cause.Learn more about our process.“Last night’s debate focused on my desire to bring balance to Washington, a desire to bring together left and right, on issues that are bipartisan in their very nature,” Dr. Oz said.Still, Dr. Oz’s allies are not being so sensitive about Mr. Fetterman’s health. A new ad from a super PAC affiliated with former President Donald J. Trump says that the Pennsylvania Democrat “just isn’t right.”During the debate, Mr. Fetterman tried to reposition his difficulties as a symbol of his grit, part of his brand as a tattooed former mayor of a battered steel town who can relate to working-class Pennsylvanians. His campaign had sought to lower expectations ahead of the clash, sending a memo to reporters that highlighted Mr. Fetterman’s challenges with auditory processing and noting that even before the stroke, debates were not his strong suit.Even as some pundits and strategists argued that skipping a debate would ultimately be forgiven, Mr. Fetterman wanted to appear, campaign officials said, because he believed Pennsylvania voters deserved an opportunity to hear from their candidates.In his opening remarks, he said of the stroke, “It knocked me down, but I’m going to keep coming back up.” He added, “This campaign is all about, to me, is about fighting for everyone in Pennsylvania that got knocked down, that needs to get back up, and fighting for all forgotten communities all across Pennsylvania that also got knocked down that needs to keep to get back up.”After the debate, his campaign said the caption system it had requested was “delayed” and “filled with errors” — a claim the media host denied.During the debate, Mr. Fetterman would not commit to releasing additional medical records. A CBS News/YouGov poll released last month found that 59 percent of registered voters in Pennsylvania believed Mr. Fetterman was healthy enough to serve.But for many voters, the debate was their first chance to watch and listen to Mr. Fetterman — or any politician who recently had a life-threatening stroke — for an extended period of time.Over the years, strokes have sidelined several senators, who have sometimes needed recoveries as long as a full year. Early this year, Senator Ben Ray Luján, Democrat of New Mexico, had a stroke, sending a jolt through his party given its narrow control of the Senate. He returned to work a month later, saying he was “90 percent” recovered.If Mr. Fetterman wins, his work in the Senate is unlikely to be significantly affected by his condition, said Senator Bob Casey, a Democrat from Pennsylvania who is supporting his bid. Mr. Casey said he had seen Mr. Fetterman rapidly improve since the summer.“He’s ready to do this job right now,” Mr. Casey said. “And I think by the time he would take the oath, he’ll be able to have then even additional recovery.”Mr. Fetterman had the stroke on the Friday before the May primary election, though he waited until Sunday to disclose it. On Primary Day, he had a pacemaker and defibrillator implanted, which his campaign described as a standard procedure that would help address “the underlying cause of his stroke, atrial fibrillation.”In a statement in early June, his cardiologist said he also had a serious heart condition called cardiomyopathy. Mr. Fetterman spent much of the summer off the campaign trail, returning in mid-August for a rally in Erie, Pa.Mr. Fetterman said during the debate that his stroke “knocked me down, but I’m going to keep coming back up.” Mehmet Oz, whose campaign mocked Mr. Fetterman’s health earlier in the race, has recently sought to focus on public safety.Nextstar Media GroupSince then, he has ramped up his appearances, regularly holding rallies and giving television interviews, and his team has been open about his lingering auditory processing challenges and his use of closed captions.This month, Mr. Fetterman released a letter from a different doctor — his primary care physician — that said “he has no work restrictions and can work full duty in public office.”Neurologists who have experience treating stroke patients with aphasia, which can disrupt a person’s ability to express speech, complimented his performance on Tuesday night.A political debate “is probably the most adversarial environment that someone with aphasia could face,” said Dr. Lee Schwamm, a vascular neurologist at Massachusetts General Hospital. “It doesn’t mean he can’t think, but his immediate ability to absorb information rapidly and deliver that canned message that all candidates practice is clearly impaired.”Disability advocates were thrilled with Mr. Fetterman’s showing, saying his appearance carried import beyond party politics by providing a positive image for the 26 percent of Americans living with disabilities.Darlene Williamson, the president of the National Aphasia Association and a speech language pathologist, praised Mr. Fetterman.“To have someone exhibit — the best word I can use is bravery — is enormously important to our families who live in a situation where people do not necessarily understand the language problems and oftentimes equate it with loss of intelligence,” she said. “And that is completely untrue.”Reporting was contributed by