Targeted delivery of antisense oligonucleotides to pancreatic β-cells

Ämmälä, Carina; Drury, William J.; Knerr, Laurent; Ahlstedt, Ingela; Stillemark-Billton, Pia; Wennberg-Huldt, C.; Andersson, Eva-Marie; Valeur, Eric; Jansson‐Löfmark, Rasmus; Janzén, David; Sundström, Linda; Meuller, Johan; Claesson, Josefine; Andersson, Patrik; Johansson, Camilla; Lee, R. G.; Prakash, Thazha P.; Seth, Punit P.; Monia, Brett P.; Andersson, Shalini

doi:10.1126/sciadv.aat3386

Cited by 144 publications

(87 citation statements)

References 31 publications

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“…It could be speculated that different GLP-1RAs might therefore behave differently in beta cells and anorectic neurons, for example, although further experiments using primary neurons and beta cells would be required to substantiate this. Moreover, there is current interest in using GPCR-targeting peptides to deliver cargo to metabolically important tissues (44)(45)(46) In summary, this work provides a systematic evaluation of a panel of GLP-1RAs with varying homology to GLP-1 and exendin-4. We identified marked differences in signalling, endocytosis and trafficking characteristics, which may be informative for the development of improved GLP-1RAs for T2D and obesity.…”

Section: Discussionmentioning

confidence: 99%

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Fang

Chen

Pickford

et al. 2020

Preprint

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Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated signalling, endocytosis and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific mid-peptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.

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Section: Discussionmentioning

confidence: 99%

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Fang

Chen

Pickford

et al. 2020

Preprint

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“…requires conjugation to an agonist ligand, which induces receptor activation and internalization. GLP1-ASO conjugates were selectively internalized into GLP1R-expressing HEK293 cells, thereby producing a 40-fold enhancement in ASO potency over the unconjugated counterpart (101). Enhanced activity was also demonstrated in isolated pancreatic islets.…”

Section: Promoting Plasma Protein Interaction and Peripheral Tissue Dmentioning

confidence: 99%

Selective tissue targeting of synthetic nucleic acid drugs

Seth¹,

Tanowitz²,

Bennett³

2019

Journal of Clinical Investigation

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“…For example, one report principally noted that GalNAc conjugation ameliorated some nephrotoxicity signals in PCSK9-targeting ASOs, with data suggesting such conjugation could be a path towards addressing oligo-induced nephrotoxicity concerns more generally [115]. Beyond GalNAc, other oligonucleotide conjugation strategies have been found effective pre-clinically in targeting specific cellular populations or promoting systemic availability, as with conjugation of a GLP1R agonist [116] or conjugation to various lipids such as cholesterol or docosahexaenoic acid (DHA, Figure 5b) [117], respectively.…”

Section: Nucleic Acid Conjugatesmentioning

confidence: 99%

Antibody Conjugates-Recent Advances and Future Innovations

et al. 2020

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Monoclonal antibodies have evolved from research tools to powerful therapeutics in the past 30 years. Clinical success rates of antibodies have exceeded expectations, resulting in heavy investment in biologics discovery and development in addition to traditional small molecules across the industry. However, protein therapeutics cannot drug targets intracellularly and are limited to soluble and cell-surface antigens. Tremendous strides have been made in antibody discovery, protein engineering, formulation, and delivery devices. These advances continue to push the boundaries of biologics to enable antibody conjugates to take advantage of the target specificity and long half-life from an antibody, while delivering highly potent small molecule drugs. While the “magic bullet” concept produced the first wave of antibody conjugates, these entities were met with limited clinical success. This review summarizes the advances and challenges in the field to date with emphasis on antibody conjugation, linker-payload chemistry, novel payload classes, absorption, distribution, metabolism, and excretion (ADME), and product developability. We discuss lessons learned in the development of oncology antibody conjugates and look towards future innovations enabling other therapeutic indications.

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Targeted delivery of antisense oligonucleotides to pancreatic β-cells

Abstract: Receptor-dependent productive uptake of GLP1-conjugated antisense oligonucleotides occurs selectively in pancreatic β-cells.

Cited by 144 publications

References 31 publications

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Selective tissue targeting of synthetic nucleic acid drugs

Antibody Conjugates-Recent Advances and Future Innovations

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