6589 Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing's Disease Article Swipe
M. Varughese
,
Hanan Eltumi
,
E. Helen Kemp
,
John Newell‐Price
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1210/jendso/bvae163.1135
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1210/jendso/bvae163.1135
Disclosure: M.S. Varughese: None. H. Eltumi: None. E.H. Kemp: None. J.D. Newell-Price: None. Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing’s Disease Background: Cushing’s disease (CD) is a multi-system disorder with high morbidity and mortality characterised by pathologically raised serum cortisol due excess expression of proopiomelanocortin (Pomc) and overproduction of ACTH by a pituitary corticotroph adenoma. Trans-sphenoidal adenomectomy is the treatment of choice, but there is a 30% recurrence rate over time. Advances in medical therapy are needed. Antisense oligonucleotides (ASOs) can silence mRNA translation by specific base-pairing. Locked nucleic acid (LNA) and 2’-O-methyl (OMe) ribose terminals make ASOs more effective by improving affinity and resistance to nuclease degradation. Aims: To investigate the effectiveness of LNA- and OMe-modified anti-Pomc ASOs at reducing ACTH secretion from murine adrenotropic tumour (AtT20) cells. To analyse the nuclease resistance of Pomc ASOs and their ability to drive an immune response. Methods: Two ASOs (ASO2 and ASO3) were designed against Pomc with phosphorothioate backbones modified with either LNA or OMe ribose terminals. These were used in lipofectamine-mediated cell transfections of AtT20 cells and ACTH in the culture medium measured by immunoassay. ASO stability was assessed by nuclease degradation assays and immunogenicity by cytokine ELISAs. Results: When compared with untreated AtT20 cells, LNA- and OMe-modified Pomc ASOs at 1 nM significantly suppressed ACTH secretion for up to 120 h and 96 h, respectively (n = 4; Unpaired t tests, all P values < 0.05). In contrast, control treatments, including scrambled and mismatched ASOs, did not cause a significant reduction. For comparison, 1 nM of ASO2-OMe, ASO2-LNA, ASO3-OMe and ASO3-LNA lowered ACTH at 24 h by 62%, 71%, 63% and 79%, respectively. Modified Pomc ASOs showed 14-31% degradation over a 120-min incubation period with 3’- and 5’-exonucleases, whilst equivalent unmodified Pomc ASOs were completely degraded. No secretion of IFN-α, IFN-β, TNF-α, IL-6 or IL-1β was detected following transfection of AtT20 cells with Pomc ASOs. Conclusions:Pomc ASOs caused significant reduction of ACTH secretion from AtT-20 cells. LNA-modified Pomc ASOs were more effective than those with OMe modifications, with neither stimulating a detectable immune response. These ASOs hold promise as a systemic therapy for Cushing’s disease. Presentation: 6/3/2024
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- Landing Page
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- OA Status
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- Related Works
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- OpenAlex ID
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All OpenAlex metadata
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https://openalex.org/W4403149309Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1210/jendso/bvae163.1135Digital Object Identifier
- Title
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6589 Antisense Oligonucleotides for Reducing ACTH Secretion in a Model of Cushing's DiseaseWork title
- Type
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articleOpenAlex work type
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enPrimary language
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2024Year of publication
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2024-10-01Full publication date if available
- Authors
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M. Varughese, Hanan Eltumi, E. Helen Kemp, John Newell‐PriceList of authors in order
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https://doi.org/10.1210/jendso/bvae163.1135Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.1210/jendso/bvae163.1135Direct OA link when available
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Cushing's disease, Secretion, Oligonucleotide, ACTH secretion, Endocrinology, Cushing Disease, Internal medicine, Disease, Medicine, Cushing syndrome, Biology, Adrenocorticotropic hormone, Biochemistry, Hormone, GeneTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.30% | 71 |
| abstract_inverted_index.63% | 275 |
| abstract_inverted_index.ASO | 190 |
| abstract_inverted_index.For | 257 |
| abstract_inverted_index.LNA | 166 |
| abstract_inverted_index.OMe | 168, 341 |
| abstract_inverted_index.Two | 151 |
| abstract_inverted_index.all | 237 |
| abstract_inverted_index.and | 37, 51, 96, 108, 120, 142, 154, 181, 198, 211, 227, 248, 265, 276, 292 |
| abstract_inverted_index.are | 80 |
| abstract_inverted_index.but | 67 |
| abstract_inverted_index.can | 85 |
| abstract_inverted_index.did | 251 |
| abstract_inverted_index.due | 45 |
| abstract_inverted_index.for | 16, 222, 358 |
| abstract_inverted_index.not | 252 |
| abstract_inverted_index.the | 63, 116, 136, 184 |
| abstract_inverted_index.was | 192, 311 |
| abstract_inverted_index.(CD) | 29 |
| abstract_inverted_index.62%, | 273 |
| abstract_inverted_index.71%, | 274 |
| abstract_inverted_index.79%, | 277 |
| abstract_inverted_index.ACTH | 18, 54, 126, 182, 220, 268, 327 |
| abstract_inverted_index.ASOs | 102, 123, 141, 152, 214, 281, 298, 322, 334, 351 |
| abstract_inverted_index.E.H. | 8 |
| abstract_inverted_index.IL-6 | 308 |
| abstract_inverted_index.J.D. | 11 |
| abstract_inverted_index.LNA- | 119, 210 |
| abstract_inverted_index.M.S. | 2 |
| abstract_inverted_index.Pomc | 140, 159, 213, 280, 297, 319, 333 |
| abstract_inverted_index.When | 204 |
| abstract_inverted_index.acid | 94 |
| abstract_inverted_index.cell | 176 |
| abstract_inverted_index.from | 128, 329 |
| abstract_inverted_index.high | 35 |
| abstract_inverted_index.hold | 352 |
| abstract_inverted_index.mRNA | 87 |
| abstract_inverted_index.make | 101 |
| abstract_inverted_index.more | 103, 336 |
| abstract_inverted_index.over | 74, 285 |
| abstract_inverted_index.rate | 73 |
| abstract_inverted_index.than | 338 |
| abstract_inverted_index.used | 173 |
| abstract_inverted_index.were | 156, 172, 299, 335 |
| abstract_inverted_index.with | 34, 160, 164, 206, 290, 318, 340, 343 |
| abstract_inverted_index.(ASO2 | 153 |
| abstract_inverted_index.(LNA) | 95 |
| abstract_inverted_index.(OMe) | 98 |
| abstract_inverted_index.3’- | 291 |
| abstract_inverted_index.ASO3) | 155 |
| abstract_inverted_index.ASOs, | 250 |
| abstract_inverted_index.ASOs. | 320 |
| abstract_inverted_index.Aims: | 113 |
| abstract_inverted_index.AtT20 | 179, 208, 316 |
| abstract_inverted_index.Kemp: | 9 |
| abstract_inverted_index.Model | 22 |
| abstract_inverted_index.None. | 4, 7, 10, 13 |
| abstract_inverted_index.These | 171, 350 |
| abstract_inverted_index.cause | 253 |
| abstract_inverted_index.cells | 180, 317 |
| abstract_inverted_index.drive | 146 |
| abstract_inverted_index.serum | 43 |
| abstract_inverted_index.their | 143 |
| abstract_inverted_index.there | 68 |
| abstract_inverted_index.those | 339 |
| abstract_inverted_index.time. | 75 |
| abstract_inverted_index.(ASOs) | 84 |
| abstract_inverted_index.(Pomc) | 50 |
| abstract_inverted_index.0.05). | 241 |
| abstract_inverted_index.14-31% | 283 |
| abstract_inverted_index.AtT-20 | 330 |
| abstract_inverted_index.IL-1β | 310 |
| abstract_inverted_index.Locked | 92 |
| abstract_inverted_index.assays | 197 |
| abstract_inverted_index.caused | 323 |
| abstract_inverted_index.cells, | 209 |
| abstract_inverted_index.cells. | 133, 331 |
| abstract_inverted_index.either | 165 |
| abstract_inverted_index.excess | 46 |
| abstract_inverted_index.immune | 148, 348 |
| abstract_inverted_index.medium | 186 |
| abstract_inverted_index.murine | 129 |
| abstract_inverted_index.period | 289 |
| abstract_inverted_index.raised | 42 |
| abstract_inverted_index.ribose | 99, 169 |
| abstract_inverted_index.showed | 282 |
| abstract_inverted_index.tests, | 236 |
| abstract_inverted_index.tumour | 131 |
| abstract_inverted_index.values | 239 |
| abstract_inverted_index.whilst | 294 |
| abstract_inverted_index.(AtT20) | 132 |
| abstract_inverted_index.120-min | 287 |
| abstract_inverted_index.Disease | 25 |
| abstract_inverted_index.ELISAs. | 202 |
| abstract_inverted_index.Eltumi: | 6 |
| abstract_inverted_index.IFN-α, | 305 |
| abstract_inverted_index.IFN-β, | 306 |
| abstract_inverted_index.TNF-α, | 307 |
| abstract_inverted_index.ability | 144 |
| abstract_inverted_index.against | 158 |
| abstract_inverted_index.analyse | 135 |
| abstract_inverted_index.choice, | 66 |
| abstract_inverted_index.control | 244 |
| abstract_inverted_index.culture | 185 |
| abstract_inverted_index.disease | 28 |
| abstract_inverted_index.lowered | 267 |
| abstract_inverted_index.medical | 78 |
| abstract_inverted_index.needed. | 81 |
| abstract_inverted_index.neither | 344 |
| abstract_inverted_index.nucleic | 93 |
| abstract_inverted_index.promise | 353 |
| abstract_inverted_index.silence | 86 |
| abstract_inverted_index.therapy | 79, 357 |
| abstract_inverted_index.&lt; | 240 |
| abstract_inverted_index.6/3/2024 | 362 |
| abstract_inverted_index.ASO3-LNA | 266 |
| abstract_inverted_index.ASO3-OMe | 264 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Advances | 76 |
| abstract_inverted_index.Methods: | 150 |
| abstract_inverted_index.Modified | 279 |
| abstract_inverted_index.Reducing | 17 |
| abstract_inverted_index.Results: | 203 |
| abstract_inverted_index.Unpaired | 234 |
| abstract_inverted_index.adenoma. | 59 |
| abstract_inverted_index.affinity | 107 |
| abstract_inverted_index.assessed | 193 |
| abstract_inverted_index.compared | 205 |
| abstract_inverted_index.cortisol | 44 |
| abstract_inverted_index.cytokine | 201 |
| abstract_inverted_index.designed | 157 |
| abstract_inverted_index.detected | 312 |
| abstract_inverted_index.disease. | 360 |
| abstract_inverted_index.disorder | 33 |
| abstract_inverted_index.measured | 187 |
| abstract_inverted_index.modified | 163 |
| abstract_inverted_index.nuclease | 111, 137, 195 |
| abstract_inverted_index.reducing | 125 |
| abstract_inverted_index.specific | 90 |
| abstract_inverted_index.systemic | 356 |
| abstract_inverted_index.ASO2-LNA, | 263 |
| abstract_inverted_index.ASO2-OMe, | 262 |
| abstract_inverted_index.Antisense | 14, 82 |
| abstract_inverted_index.Secretion | 19 |
| abstract_inverted_index.anti-Pomc | 122 |
| abstract_inverted_index.backbones | 162 |
| abstract_inverted_index.contrast, | 243 |
| abstract_inverted_index.degraded. | 301 |
| abstract_inverted_index.effective | 104, 337 |
| abstract_inverted_index.following | 313 |
| abstract_inverted_index.improving | 106 |
| abstract_inverted_index.including | 246 |
| abstract_inverted_index.morbidity | 36 |
| abstract_inverted_index.mortality | 38 |
| abstract_inverted_index.pituitary | 57 |
| abstract_inverted_index.reduction | 325 |
| abstract_inverted_index.response. | 149, 349 |
| abstract_inverted_index.scrambled | 247 |
| abstract_inverted_index.secretion | 127, 221, 303, 328 |
| abstract_inverted_index.stability | 191 |
| abstract_inverted_index.terminals | 100 |
| abstract_inverted_index.treatment | 64 |
| abstract_inverted_index.untreated | 207 |
| abstract_inverted_index.Varughese: | 3 |
| abstract_inverted_index.completely | 300 |
| abstract_inverted_index.detectable | 347 |
| abstract_inverted_index.equivalent | 295 |
| abstract_inverted_index.expression | 47 |
| abstract_inverted_index.incubation | 288 |
| abstract_inverted_index.mismatched | 249 |
| abstract_inverted_index.recurrence | 72 |
| abstract_inverted_index.reduction. | 256 |
| abstract_inverted_index.resistance | 109, 138 |
| abstract_inverted_index.suppressed | 219 |
| abstract_inverted_index.terminals. | 170 |
| abstract_inverted_index.unmodified | 296 |
| abstract_inverted_index.Background: | 26 |
| abstract_inverted_index.Cushing’s | 24, 27, 359 |
| abstract_inverted_index.Disclosure: | 1 |
| abstract_inverted_index.comparison, | 258 |
| abstract_inverted_index.degradation | 196, 284 |
| abstract_inverted_index.investigate | 115 |
| abstract_inverted_index.significant | 255, 324 |
| abstract_inverted_index.stimulating | 345 |
| abstract_inverted_index.translation | 88 |
| abstract_inverted_index.treatments, | 245 |
| abstract_inverted_index.LNA-modified | 332 |
| abstract_inverted_index.OMe-modified | 121, 212 |
| abstract_inverted_index.adenomectomy | 61 |
| abstract_inverted_index.adrenotropic | 130 |
| abstract_inverted_index.corticotroph | 58 |
| abstract_inverted_index.degradation. | 112 |
| abstract_inverted_index.immunoassay. | 189 |
| abstract_inverted_index.multi-system | 32 |
| abstract_inverted_index.respectively | 230 |
| abstract_inverted_index.transfection | 314 |
| abstract_inverted_index.2’-O-methyl | 97 |
| abstract_inverted_index.Newell-Price: | 12 |
| abstract_inverted_index.Presentation: | 361 |
| abstract_inverted_index.base-pairing. | 91 |
| abstract_inverted_index.characterised | 39 |
| abstract_inverted_index.effectiveness | 117 |
| abstract_inverted_index.respectively. | 278 |
| abstract_inverted_index.significantly | 218 |
| abstract_inverted_index.transfections | 177 |
| abstract_inverted_index.immunogenicity | 199 |
| abstract_inverted_index.modifications, | 342 |
| abstract_inverted_index.overproduction | 52 |
| abstract_inverted_index.pathologically | 41 |
| abstract_inverted_index.Conclusions:Pomc | 321 |
| abstract_inverted_index.Oligonucleotides | 15 |
| abstract_inverted_index.Trans-sphenoidal | 60 |
| abstract_inverted_index.oligonucleotides | 83 |
| abstract_inverted_index.phosphorothioate | 161 |
| abstract_inverted_index.5’-exonucleases, | 293 |
| abstract_inverted_index.proopiomelanocortin | 49 |
| abstract_inverted_index.lipofectamine-mediated | 175 |
| cited_by_percentile_year | |
| countries_distinct_count | 1 |
| institutions_distinct_count | 4 |
| citation_normalized_percentile.value | 0.30254205 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |