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Tag: Cystic Fibrosis

  • Cystic fibrosis drug found to be safe and effective in newborns

    Cystic fibrosis drug found to be safe and effective in newborns

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    A Cystic Fibrosis drug targeting the basic defect that causes the condition has been shown to be safe and effective in newborns aged four weeks and above, new research involving RCSI University of Medicine and Health Sciences and Children’s Health Ireland has found.

    The finding is described as a ‘huge moment’ for Cystic Fibrosis by one of the lead researchers. The study included the first baby in the world with Cystic Fibrosis to be diagnosed from birth and enrolled directly onto a trial of this sort.

    The drug, Ivacaftor (Kalydeko), is the first drug designed to treat the basic defect in Cystic Fibrosis. It was originally approved for adults, then sequentially over several years for older and younger children. Currently, it is approved for babies aged four months and older, however, this new research suggests that it is safe and effective for babies as young as four weeks of age.

    Cystic Fibrosis experts predict that the earlier treatments can begin, the more likely that progression of the condition can be slowed down or halted in children, and this is the focus of several international research studies led by RCSI and Children’s Health Ireland. The findings of this study could pave the way for eligible newborns to start treatment on the medicine at the time of diagnosis (typically at newborn screening) rather than having to wait until they are four months old.

    “This is a huge moment in Cystic Fibrosis,” said Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study, which was published in the Journal of Cystic Fibrosis.

    Over the years Ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age. This is an important development because almost all children are diagnosed through newborn screening at around this time. The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families.”


     Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI

    Cystic Fibrosis is an inherited disease that mainly affects the lungs and digestive system. Ireland has the highest incidence of the condition in the world: approximately 1,400 children and adults in Ireland live with the condition and more than 30 new cases of

    Cystic Fibrosis are diagnosed here each year, typically around 4 weeks of age through the newborn screening program.

    In recent years, new medicines have emerged that target the basic defect that causes Cystic Fibrosis. Ivacaftor (Kalydeko) is one such treatment. It targets a genetic change seen in around 4% of people with Cystic Fibrosis worldwide, and around 10% in Ireland.

    Siblings Kara (aged 5) and Isaac Moss (aged 2) both participated in the study through Children’s Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.

    Isaac was the first baby with Cystic Fibrosis in the world to be diagnosed from birth and enrolled directly onto a trial of these ground-breaking treatments.

    “Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of Cystic Fibrosis at the moment,” said their mother Debbie.

    “Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future”

    Ivacaftor is manufactured by pharmaceutical company Vertex Pharmaceuticals, who are currently applying to the European Medicines Agency for an extension to the marketing authorization for Ivacaftor down to one month of age.

    The study, ‘Safety and efficacy of Ivacaftor in infants aged 1 to less than 4 months with Cystic Fibrosis’, is published in the Journal of Cystic Fibrosis and involved researchers from RCSI, Children’s Health Ireland, the USA and the UK.

    Source:

    RCSI University of Medicine and Health Sciences

    Journal reference:

    McNally, P., et al. (2024) Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis. Journal of Cystic Fibrosis. doi.org/10.1016/j.jcf.2024.03.012.

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  • Researchers take important step toward genetic therapy for hereditary conditions

    Researchers take important step toward genetic therapy for hereditary conditions

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    Researchers who work with tiny drug carriers known as lipid nanoparticles have developed a new type of material capable of reaching the lungs and the eyes, an important step toward genetic therapy for hereditary conditions like cystic fibrosis and inherited vision loss.

    Findings of the study led by Gaurav Sahay and Yulia Eygeris of the Oregon State University College of Pharmacy and Renee Ryals of Oregon Health & Science University were published today in the Proceedings of the National Academy of Sciences.

    Unlike other types of lipid nanoparticles that tend to accumulate in the liver, the ones in this study, based on the compound thiophene, are able to navigate their way to the tissues of the lungs and retina, where they deliver their therapeutic payload. The researchers refer to these new lipids as Thio-lipids.

    The collaboration demonstrated, by using animal models, the possibility of using Thio-lipids in lipid nanoparticles to deliver messenger RNA, the technology underpinning COVID-19 vaccines, to combat genetic blindness and pulmonary disease.

    These nanoparticles filled with fatty lipids can encapsulate genetic medicines like mRNA and CRISPR-Cas9 gene editors, which can be used to treat and even cure rare genetic diseases. Chemical structures of the lipids determine how potent are the lipid nanoparticles and which organ they can reach from the bloodstream.”


    Yulia Eygeris, senior research associate at OSU

    Lipids are organic compounds containing fatty tails and are found in many natural oils and waxes, and nanoparticles are tiny pieces of material ranging in size from one- to 100-billionths of a meter. Messenger RNA delivers instructions to cells for making a particular protein.

    With the coronavirus vaccines, the mRNA carried by the lipid nanoparticles instructs cells to make a harmless piece of the virus’ spike protein, which triggers an immune response from the body. 

    As a therapy for vision impairment resulting from inherited retinal degeneration, the mRNA would instruct cells in the retina – which don’t work right because of a genetic mutation – to manufacture the proteins needed for sight. Inherited retinal degeneration, commonly abbreviated to IRD, encompasses a group of disorders of varying severity and prevalence that affect one out of every few thousand people worldwide.

    An example of a genetic pulmonary condition is cystic fibrosis, a progressive 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.

    One faulty gene – the cystic fibrosis transmembrane conductance regulator, or CFTR – causes the disease, which is characterized by lung dehydration and mucus buildup that blocks the airway.

    The thiophene-based lipid nanoparticle study, which involved mice and non-human primates, stems from a $3.2 million grant to Sahay and Ryals from the National Eye Institute. The grant’s purpose is addressing limitations associated with the current primary means of delivery for gene editing: a type of virus known as adeno-associated virus, or AAV.

    “AAV has limited packaging capacity compared to lipid nanoparticles and it can prompt an immune system response,” said Sahay, a professor of pharmaceutical sciences. “It also doesn’t do fantastically well in continuing to express the enzymes the editing tool uses as molecular scissors to make cuts in the DNA to be edited.”

    Sahay calls the Thio-lipid findings “highly encouraging” but says more studies are needed, including research on the lipids’ long-term impact on retinal health.

    “But we think our results serve as a proof of concept and we will continue to explore Thio-lipids in potential treatments of pulmonary and retinal genetic diseases,” he said.

    Other OSU College of Pharmacy researchers contributing to the study were Mohit Gupta, Jeonghwan Kim, Antony Jozic, Milan Gautam, Jonas Renner, Dylan Nelson and Elissa Bloom.

    In addition to the National Eye Institute, funding and research support were provided by the Oregon National Primate Research Center and the Casey Eye Institute.

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  • Penn engineers develop targeted lung delivery system using lipid nanoparticles

    Penn engineers develop targeted lung delivery system using lipid nanoparticles

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    Penn Engineers have developed a new means of targeting the lungs with lipid nanoparticles (LNPs), the miniscule capsules used by the Moderna and Pfizer-BioNTech COVID-19 vaccines to deliver mRNA, opening the door to novel treatments for pulmonary diseases like cystic fibrosis. 

    In a paper in Nature Communications, Michael J. Mitchell, Associate Professor in the Department of Bioengineering, demonstrates a new method for efficiently determining which LNPs are likely to bind to the lungs, rather than the liver.

    The way the liver is designed. LNPs tend to filter into hepatic cells, and struggle to arrive anywhere else. Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis.”


    Michael J. Mitchell, Associate Professor, Department of Bioengineering, Penn

    Previous studies have shown that cationic lipids -; lipids that are positively charged -; are more likely to successfully deliver their contents to lung tissue. “However, the commercial cationic lipids are usually highly positively charged and toxic,” says Lulu Xue, a postdoctoral fellow in the Mitchell Lab and the paper’s first author. Since cell membranes are negatively charged, lipids with too strong a positive charge can literally rip apart target cells. 

    Typically, it would require hundreds of mice to individually test the members of a “library” of LNPs -; chemical variants with different structures and properties -; to find one with a low charge that has a higher likelihood of delivering a medicinal payload to the lungs.

    Instead, Xue, Mitchell and their collaborators used what is known as “barcoded DNA” (b-DNA) to tag each LNP with a unique strand of genetic material, so that they could inject a pool of LNPs into just a handful of animal models. Then, once the LNPs had propagated to different organs, the b-DNA could be scanned, like an item at the supermarket, to determine which LNPs wound up in the lungs. 

    After identifying an LNP that successfully penetrated lung cells, Xue, Mitchell and their collaborators administered the molecule to mice suffering from lung cancer: the treatment had a pronounced and positive effect, drastically reducing tumor size by delivering a strand of mRNA and gRNA that suppresses the growth of lung tumors.

    “This technology will help to accelerate the development of mRNA therapeutics beyond the liver,” says Xue, pointing to the speed, low cost and efficacy of the technique. 

    This study was conducted at the University of Pennsylvania School of Engineering and Applied science and supported by a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Science Foundation CAREER Award (CBET-2145491) and an American Cancer Society Research Scholar Grant (RSG-22-122-01-ET).

    Other co-authors include Alex G. Hamilton, Rakan El-Mayta, Xuexiang Han, Ningqiang Gong, Junchao Xu, Christian G. Figueroa-Espada, Sarah J. Shepherd and Alvin J. Mukalel of Penn Engineering; Gan Zhao, Zebin Xiao and Andrew E. Vaughan of Penn Vet; Xinhong Xiong and Jiaxi Cui of Yangtze Delta Region Institute (Huzhou); Karin Wang of Temple University; and Mohamed-Gabriel Alameh and Drew Weissman of the Perelman School of Medicine at Penn.

    Source:

    University of Pennsylvania School of Engineering and Applied Science

    Journal reference:

    Xue, L., et al. (2024). High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models. Nature Communications. doi.org/10.1038/s41467-024-45422-9.

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