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Cystic Fibrosis Foundation To Fund Development Of Breath Test For Pseudomonas Infections
The UK Health Security Agency (HSA) today published a new priority pathogens tool—outlining pathogen families that pose the biggest risk to public health—to help support funding of research and development into new diagnostics, vaccines, and treatments.
NIAID/Flickr cc The list contains 24 pathogen families, providing rankings of high, moderate, or low regarding pandemic and epidemic potential. The HSA said its scientists took into account transmission routes and disease severity.
In a statement, the agency said the ratings aren't intended as a detailed threat assessment and don't indicate which pathogen is most likely to trigger then next pandemic, but rather which ones require increased scientific investments and study. The rankings also highlight which pathogens need increased diagnostics and vaccine development and which may be exacerbated by changing climate or antimicrobial resistance. Officials said the tool will be updated, based on scientific developments.
Pathogens with high pandemic potential include coronaviruses, the Orthomyxoviridae group that includes avian flu, the Paramyxoviridae group that includes Nipah virus, and the Picornaviridae that includes enterovirus D68.
Expert reactions mixedScientists contacted by Britain's Science Media Centre, an independent group that works to provide evidence-based clarity on scientific topics, had mixed reviews about the new tool.
Some said it brings useful information together in one place, and Catrin Moore, DPhil, MBA, MPH, an infectious disease and global health specialist with the University of London, said she would like to know more about how the HAS's methodology, the papers it used, and the diagnostics it identified.
Jose Vazquez-Boland, DVM, PhD, chair of infectious diseases at the University of Edinburgh, said the priority list comes with a risk, given that other important pathogens might be receive insufficient or no funding when funding and resources are increasingly scarce. "In my opinion, the bacterial pathogens list is rather limited and predictable," he said.
Breathing New Life: Working Toward An Inhalable Gene Therapy For Cystic Fibrosis
Imagine a future where treating cystic fibrosis is as simple as taking a deep breath. That's exactly what a team of pediatric physician-scientists at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA is working to achieve.
Cystic fibrosis is a life-threatening genetic disease that clogs the lungs with thick, sticky mucus, leading to chronic infections and severe organ damage. Despite breakthrough medications that have been transformative for some, the drugs come with significant limitations: they don't work for everyone, can cost millions over a lifetime and, most critically, don't address the root cause of the condition. Without a curative treatment, the disorder remains a ticking clock for patients who don't respond to existing drugs, many of whom face respiratory failure by their 30s or 40s.
The disease is caused by mutations in one gene — cystic fibrosis transmembrane conductance regulator, or CFTR — making it, in theory, an ideal candidate for gene-editing technology. However, there's a unique challenge of delivering a gene therapy to the target lung stem cells in cystic fibrosis, said Dr. Donald Kohn, a gene therapy pioneer who has successfully developed therapies for other single-gene disorders like severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID.
"It's like trying to get into Fort Knox," said Kohn, a UCLA distinguished professor of microbiology, immunology and molecular genetics. "There are multiple barriers — thick mucus, inflammation and the cells' location at the bottom of the airway."
To overcome these obstacles, he has joined forces with lung disease expert Dr. Brigitte Gomperts and nanotechnologist Dr. Steven Jonas. They're combining their diverse expertise to develop a targeted gene-editing system that can deliver a one-time treatment through a simple inhalable mist.
"Think about it like breathing in a CRISPR-Cas9 gene-editing package," said Jonas, an assistant professor of pediatrics at UCLA.
New hope for cystic fibrosis patients without treatment optionsGomperts has always been driven by a simple goal: finding better treatments for her patients.
That pursuit has led her to spend over 20 years studying stem cells of the airway, which are lung stem cells nestled deep within the airway walls that serve as targets for gene correction in the impacted lungs.
"These are the cells that continuously renew and generate the specialized cells responsible for keeping mucus hydrated and the airways clear," Gomperts, a professor of pediatrics and pulmonary medicine at UCLA, explained.
Although cystic fibrosis is a single gene mutation, there are more than 1,000 different ways the CFTR gene can mutate in patients. When functioning properly, this gene produces a protein that regulates the vital flow of water in and out of the lung stem cells, maintaining mucus at the right consistency.
In cystic fibrosis, mutations in the gene either produce proteins that don't work properly or, in more severe cases, prevent protein production entirely.
The currently available "miracle" drugs work only when there are some proteins to fix. For the 10%–20% of patients with null mutations who produce no protein at all, these medications offer no benefit.
These null mutations are known, and the Kohn lab is testing different gene-editing strategies to correct them.
"If you think of a sentence with 50 letters, any letter that's out of place will make the sentence nonsense," Kohn said. "We're moving forward with two approaches — fixing all the letters that are out of place by adding in a normal CFTR gene to override the inactive gene and developing methods to fix each of these mutations individually. We'll then evaluate what's most effective."
How nanotechnology is enabling gene editing for cystic fibrosisWhile Kohn optimizes the gene-editing method, Jonas and his team are tackling the critical challenge of delivery: ensuring the gene-editing machinery reaches the lung stem cells, where the correction could last a lifetime.
Their solution harnesses the power of lipid nanoparticles — tiny molecular carriers designed to transport the gene-editing cargo directly where they're needed.
"Think of it like an Amazon delivery," Jonas said. "Our nanoparticles are the packaging that helps transport the gene-editing machinery while shielding it from the body's defenses."
Ruby Sims, a postdoctoral scholar in the Jonas lab, said it's of highest importance to target a precise location.
"It's not just about dropping off a package anywhere in the lungs," she said. "We need to deliver it to the right ZIP code, the right street, the right house. That's what our nanoparticles are engineered to do."
The team envisions delivering the therapy through an inhaler. Once administered, the nanoparticles would travel deep into the airways, delivering the gene-editing tools directly to the lung stem cells, where they can make a permanent repair.
Working collaboratively toward a cure for cystic fibrosisFor years, Gomperts, Kohn and Jonas have worked side by side in the pediatrics department treating children with cancer and blood disorders. But it took a chance lunch at the center's annual Stem Cell Symposium to bring them together on this project.
"I was really taken with this idea of gene therapy for cystic fibrosis and found myself sitting there thinking, 'Wow, I've got the exact experts who could actually make this happen,'" Gomperts recalled. "You have to know which cells you're targeting, how to reach them and the best way to fix the faulty gene, and among the three of us, we had all the pieces of the puzzle."
The UCLA Broad Stem Cell Research Center kickstarted the collaborative project with seed funding through its Innovation Awards Program. Promising preliminary results have since helped the team secure additional support from the California Institute for Regenerative Medicine, the Cystic Fibrosis Research Institute and the Cystic Fibrosis Foundation, helping move the project toward preclinical testing.
A platform to treat other genetic diseasesWhile the team's initial target is cystic fibrosis, the nanoparticle platform could be a transformative tool for treating other genetic lung diseases and even conditions like muscular dystrophy and sickle cell disease.
"Science is also the most fun when you're tackling these difficult problems together."
UCLA distinguished professor of microbiology, immunology and molecular genetics Dr. Donald Kohn
"The beauty of this approach is its modularity — it's like Legos," Jonas said. "We can swap in different gene-editing machinery and use the same delivery strategy to target and correct different genes."
For now, the researchers remain united by their mission to develop a one-time treatment that offers lasting benefits for patients with cystic fibrosis.
"Science is complicated, so multidisciplinary teams are the way to do it," Kohn said. "Science is also the most fun when you're tackling these difficult problems together."
Newly Uncovered Mechanism Could Drive Next-gen Cystic Fibrosis Treatments
A new study from The Hospital for Sick Children (SickKids) reveals the process underlying protein organization on cell membranes, a finding which could pave the way for innovative cystic fibrosis treatments.
Cystic fibrosis (CF) is a genetic condition that affects the lungs, pancreas and other organs, caused by variations on the cystic fibrosis transmembrane conductance regulator?(CFTR) gene. There are around 700 known variants that cause CF, but current treatments address only a few, and none offer a cure.
"Therapeutics for cystic fibrosis have hit a plateau, demanding that we uncover new ways of looking at the science behind the condition. By studying protein organization, we've uncovered a brand-new avenue for developing therapeutics for cystic fibrosis," says Dr. Jonathon Ditlev, Scientist in the Molecular Medicine and Cell & Systems Biology programs.
Phase separation key to CFTR protein
Rather than looking solely at the function of the CFTR protein, the study, published in Proceedings of the National Academy of Sciences (PNAS), examined how CFTR proteins are organized on the cell membrane. In healthy children, the proteins form clusters, helping to regulate water and salt intake. In people with CF, those clusters are disrupted.
The process that forms the clusters is called phase separation, a well-known process that has recently been appreciated for its role in biological organization and that Dr. Julie Forman-Kay, Program Head and Senior Scientist in the Molecular Medicine program and co-lead author of the paper, proposed might be relevant to CFTR in 2017.
"Our findings establish CFTR as a phase-separating protein, opening up a previously unexplored mode of protein regulation and a new target for future therapies," explains Forman-Kay.
The future of CF therapeutics -- inspired by the past
The research team is already working with other SickKids scientists, including Dr. Christine Bear, Co-Director of the Cystic Fibrosis Centre, to explore ways to advance this research into novel therapies for CF.
"Current therapies for cystic fibrosis are effective for most children, but not all," says Bear, who is also a Senior Scientist in the Molecular Medicine program. "These findings could help us target those for whom current therapies remain ineffective, while also bolstering outcomes for all those affected by CF."
While the study could inform the next generation of CF therapeutics and advance Precision Child Health at SickKids, Ditlev joined SickKids without any thought of researching CF -- but that quickly changed.
"Being a part of the SickKids, with its storied history of research excellence impacting patients with cystic fibrosis, I realized how my experience and tools could contribute to and enhance this legacy."
This research was funded by the Natural Sciences and Engineering Research Council (NSERC), the National Institutes of Health (NIH) and Cystic Fibrosis Canada.
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