Oligonucleotide Therapies for the Lung: Ready to Return to the Clinic?

Kumar, Manish; Moschos, Sterghios A.

doi:10.1016/j.ymthe.2017.11.002

Cited by 12 publications

(12 citation statements)

References 20 publications

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“…Based on our results, we aim to develop an inhaled ASO drug, for increased lung exposure with minimal systemic exposure. Previous studies showed that inhaled ASOs are widely distributed and active in mice and non-human primates lungs, reaching even the most distal (alveolar) regions, with minimal systemic exposure and good tolerability as well as high stability with an estimated halflife of 13-14 days following a single ASO exposure [47][48][49][50] . Importantly, in a recent study, Crosby et al demonstrated that ASOs dissolved in saline traverse CF-like mucus and distribute throughout mouse lung [51] .…”

Section: Discussionmentioning

confidence: 99%

“…Analyzing the effect of the different chemically modified ASOs on the splicing pattern supported the functional results. The effect of SPL84-23 carrying the 2 -MOE modification on the splicing pattern was more efficient than that of the 2 -OMe modification, as demonstrated by a significant reduction in the level of aberrantly spliced transcripts already at 50 relation was performed and the EC50 and maximal effect (efficacy) were calculated. As presented, treatment with SPL84-23 carrying the 2 -MOE modification resulted in an increased potency and efficacy over the 2 -OMe modification as reflected by the ability to shift the ratio between the aberrantly and correctly spliced CFTR transcripts at lower concentrations (Supplementary Figure 8A) and the lower EC50 value (Supplementary Figure 8B).…”

Section: Optimization Of Spl84-23 Potency By Chemical Modificationsmentioning

confidence: 99%

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Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Oren

Sinai

Golec

et al. 2021

Journal of Cystic Fibrosis

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Background: Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849 + 10 kb C-to-T splicing mutation in the CFTR gene. Methods:We have screened, in FRT cells expressing the 3849 + 10 kb C-to-T splicing mutation, ~30 2 -O-Methyl-modified phosphorothioate ASOs, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The effect of highly potent ASO candidates on the splicing pattern, protein maturation and CFTR function was further analyzed in well differentiated primary human nasal and bronchial epithelial cells, derived from patients carrying at least one 3849 + 10 kb C-to-T allele.Results: A highly potent lead ASO, efficiently delivered by free uptake, was able to significantly increase the level of correctly spliced mRNA and completely restore the CFTR function to wild type levels in cells from a homozygote patient. This ASO led to CFTR function with an average of 43% of wild type levels in cells from various heterozygote patients. Optimized efficiency of the lead ASO was further obtained with 2 -Methoxy Ethyl modification (2 MOE). Conclusion:The highly efficient splicing modulation and functional correction, achieved by free uptake of the selected lead ASO in various patients, demonstrate the ASO therapeutic potential benefit for CF patients carrying splicing mutations and is aimed to serve as the basis for our current clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: Optimization Of Spl84-23 Potency By Chemical Modificationsmentioning

confidence: 99%

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Oren

Sinai

Golec

et al. 2021

Journal of Cystic Fibrosis

View full text Add to dashboard Cite

show abstract

“…Based on our results, we aim to develop an inhaled ASO drug, for increased lung exposure with minimal systemic exposure. Previous studies showed that inhaled ASOs are widely distributed and active in mice and non-human primates lungs, reaching even the most distal (alveolar) regions, with minimal systemic exposure and good tolerability (40)(41)(42)(43). Importantly, in a recent study, Crosby et al demonstrated that ASOs dissolved in saline traverse CF-like mucus and distribute throughout mouse lung (44).…”

Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation

Oren

Sinai

Golec

et al. 2021

Preprint

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Antisense oligonucleotide (ASO)-based drugs for splicing modulation were recently been approved for various genetic diseases with unmet need. Here we aimed to develop an ASO-based splicing modulation therapy for Cystic Fibrosis (CF) patients carrying the 3849+10kb C-to-T splicing mutation in the CFTR gene. We have screened, in FRT cells expressing this mutation, ~30 ASOs chemically modified with 2-O-Methyl on a phosphrothioate backbone, targeted to prevent the recognition and inclusion of a cryptic exon generated due to the mutation. The screening identified five ASO candidates able to promote CFTR correct splicing and rescue channel activity. Further analyses in well differentiated primary human nasal and bronchial epithelial cells (HNEs, HBEs), derived from patients carrying at least one 3849+10kb C-to-T allele, led to the identification of a highly potent lead ASO. The ASO was efficiently delivered by free uptake into patients' HNEs and HBEs and completely restored CFTR function to wild type levels in cells from a homozygous patient and led to an average of 43% of wild type levels in cells from various heterozygous patients. Optimized efficiency was further obtained with 2-Methoxy Ethyl chemical modification. The results demonstrate the therapeutic potential and clinical benefit of ASO-based splicing modulation for genetic diseases caused by splicing mutations.

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“…Other relatively large molecules including antisense oligonucleotides (ASO) also have been and are being evaluated to treat local lung diseases such as asthma and CF to exploit the relatively low absorption into blood and extended lung retention. Alton et al 50 and Kumar and Moschos 51 in reviews of inhaled oligonucleotide therapies have noted the issue of accumulation of alveolar macrophages and some inflammation noted at high doses in toxicology studies. Kumar and Moschos 51 cite new innovations by Crosby et al 52 and note that if lung ASO therapies with improved targeting can be developed, the liability of macrophage accumulation may be diminished.…”

Section: Mechanisms Of Absorption and Clearance For Proteins And Biolmentioning

confidence: 99%

Perspectives on Lung Dose and Inhaled Biomolecules

Wolff¹

2020

Toxicol Pathol

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Dose is highly important to studies of inhaled agents because there must be an understanding of the dose delivered to humans, the dose delivered to animals in toxicology studies, and an ability to interpret and compare both sets of information relative to safety. Unlike oral or intravenous administrations, total delivered or inhaled dose is not easy to determine following inhalation exposure and is also not necessarily the most important determinant of toxicity. A review of dose distribution throughout the respiratory tract as well as total inhaled dose is provided. The implications of regional deposition for biologics are reviewed and specific examples over a range of different molecular weights are provided. Biologics are generally large enough that absorption from ciliated epithelia is low. Thus, deposition of biologics in head airways and tracheobronchial regions is unlikely to be of high importance unless there are interactions with specific receptors at these sites. Therefore, it is the dose of proteins or biologics deposited in the alveolar region that are generally of most interest.

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Oligonucleotide Therapies for the Lung: Ready to Return to the Clinic?

Cited by 12 publications

References 20 publications

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation

Perspectives on Lung Dose and Inhaled Biomolecules

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