Pulmonary drug delivery technology enables anakinra repurposing in cystic fibrosis

Puccetti, Matteo; Pariano, Marilena; Stincardini, Claudia; Wojtylo, Paulina; Schoubben, Aurelie Marie Madeleine; Nunzi, E.; Ricci, Maurizio; Romani, Luigina; Giovagnoli, Stefano

doi:10.1016/j.jconrel.2022.11.043

Cited by 8 publications

(4 citation statements)

References 40 publications

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“…It would be therefore important to restrict SPL inhibition to the lung where S1P levels are decreased. This approach has already been applied by our group to deliver anti-inflammatory agents directly into the lungs in a CF setting to optimize the efficacy/safety profile 72 – 74 .…”

Section: Discussionmentioning

confidence: 99%

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Cellini,

Pampalone,

Camaioni

et al. 2023

Sci Rep

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Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

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Section: Discussionmentioning

confidence: 99%

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Cellini,

Pampalone,

Camaioni

et al. 2023

Sci Rep

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“…Polymyxin B NPs complexed with polystyrene sulfonates of different relative molecular masses showed a 10,000-fold increase in PA inhibition [ 306 ]. Matteo et al [ 307 ] successfully developed an inhalable anakinra dry powder to meet the specific requirements of pulmonary drug delivery ( Fig. 11 B).…”

Section: Application Of Pulmonary Drug Deliverymentioning

confidence: 99%

“…Adapted reprinted with permission from Ref. [ 307 ] (License number: 5,682,830,851,672). (C) Laser confocal scanning microscopy images of (i) untreated PAO1-infected CFBE410 versus and (ii) CFBE410 treated with Tobramycin Monoolein-liquid crystal NPs nebulization.…”

Section: Application Of Pulmonary Drug Deliverymentioning

confidence: 99%

Pulmonary inhalation for disease treatment: Basic research and clinical translations

Wang,

Yang

et al. 2024

Materials Today Bio

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“…Peripheral side effects, such as neutropenia and inhibition of inflammatory signaling pathways in the spleen, were not observed and correlated with the lower serum levels compared to the parenteral injection. Importantly, a rough estimation of the human equivalent dose corresponding to the maximum dose employed in our study showed that this value is about half of the daily clinically prescribed systemic dose of anakinra [ 63 ]. Therefore, our results provide a proof-of-concept demonstration of the prspective potential of anakinra repurposing in CF via the pulmonary route at a reduced dosage and reduced risk of side effects.…”

Section: Targeted Delivery For Drug Repurposing: the Case Of Anakinramentioning

confidence: 99%

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

et al. 2023

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Developing therapeutics for inflammatory diseases is challenging due to physiological mucosal barriers, systemic side effects, and the local microbiota. In the search for novel methods to overcome some of these problems, drug delivery systems that improve tissue-targeted drug delivery and modulate the microbiota are highly desirable. Microbial metabolites are known to regulate immune responses, an observation that has resulted in important conceptual advances in areas such as metabolite pharmacology and metabolite therapeutics. Indeed, the doctrine of “one molecule, one target, one disease” that has dominated the pharmaceutical industry in the 20th century is being replaced by developing therapeutics which simultaneously manipulate multiple targets through novel formulation approaches, including the multitarget-directed ligands. Thus, metabolites may not only represent biomarkers for disease development, but also, being causally linked to human diseases, an unexploited source of therapeutics. We have shown the successful exploitation of this approach: by deciphering how signaling molecules, such as the microbial metabolite, indole-3-aldehyde, and the repurposed drug anakinra, interact with the aryl hydrocarbon receptor may pave the way for novel therapeutics in inflammatory human diseases, for the realization of which drug delivery platforms are instrumental.

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Pulmonary drug delivery technology enables anakinra repurposing in cystic fibrosis

Cited by 8 publications

References 40 publications

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Dual species sphingosine-1-phosphate lyase inhibitors to combine antifungal and anti-inflammatory activities in cystic fibrosis: a feasibility study

Pulmonary inhalation for disease treatment: Basic research and clinical translations

Turning Microbial AhR Agonists into Therapeutic Agents via Drug Delivery Systems

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