A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice

Tachas, George; Lofthouse, Shari; Wraight, Christopher J.; Baker, Brenda F.; Sioufi, Namir; Jarres, R A; Berdeja, Andrés; Rao, A M; Kerr, Linda M.; D'Aniello, E; Waters, Michael J.

doi:10.1677/joe.1.06553

Cited by 22 publications

(12 citation statements)

References 19 publications

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“…Theoretically, this could be accomplished by the construction of GH receptor antagonists and by RNA antisense techniques, thus preventing the synthesis of the GH receptor. Indeed, the recently developed antisense oligonucleotide, ATL 227446, effectively inhibited hepatic GH receptor expression and IGF-I production and decreased body weight gain in mice (Tachas et al 2006). Below we shall review the molecular structure of GH and its receptor and physiology which all are keystones for the development of GH receptor antagonists.…”

Section: Gh Antagonistsmentioning

confidence: 99%

Nanomedicines in the treatment of acromegaly: focus on pegvisomant

Roelfsema¹,

Biermasz²,

Pereira³

et al. 2006

International Journal of Nanomedicine

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This article examines the role of pegvisomant in the treatment of acromegaly. This syndrome, caused by excessive growth hormone (GH) secretion by a pituitary adenoma, is associated with a doubled mortality rate and poor quality of life. Pituitary microsurgery has long been the fi rst choice of treatment since it cures many patients, especially those with localized tumors. Adjuvant irradiation was given if insulin-like growth factor-I (IGF-I) or GH did not normalize. The introduction of long-acting slow-release somatostatin analogs was a breakthrough for adjuvant treatment, although not always effective. Rather, targeting excessive GH production, muting the GH signal at its receptor, was a totally different approach. The development of GH antagonists (by mutation of glycine at position 120) and other modifi cations to enhance receptor binding, and subsequent pegylation of the molecule led to the development of B2036. After pegylation of B2036 at 5 positions the distribution volume is restricted and its serum half-life considerably increased. In short-term clinical studies performed in selected, mostly pretreated, acromegalic patients, IGF-I normalized in the majority of cases. Combination therapy with long-acting somatostatin analogs and weekly rather than daily pegvisomant injections appears to be successful in one clinical study and might limit the high cost of pegvisomant. Long-term effi cacy and safety has to be demonstrated. The drug does not cross the blood-brain barrier, and whether it distributes freely into the extracellular space of other organs than the liver has not been investigated, which might have implications for persistent local IGF-I production under unrestrained GH concentrations.

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Section: Gh Antagonistsmentioning

confidence: 99%

Nanomedicines in the treatment of acromegaly: focus on pegvisomant

Roelfsema¹,

Biermasz²,

Pereira³

et al. 2006

International Journal of Nanomedicine

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“…Studies in experimental animals have shown promising results in the control of diabetic nephropathy and a variety of cancers, and clinical studies in this area are certainly warranted [11]. We have recently reported that an alternative to pegvisomant, modified antisense oligonucleotides to the GHR, is able to lower serum IGF-1 in mice to similar levels as pegvisomant, and inhibits long-term body weight gain in mice [31]. These remain to be clinically tested.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Growth Hormone Receptor Function and Clinical Implications

Lichanska

Waters²

2008

Horm Res Paediatr

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Although used as a therapeutic for 50 years, it is only recently that the application of molecular techniques has provided a basis for understanding growth hormone’s (GH) clinical actions. This article reviews progress in our current knowledge of the molecular mechanism of growth hormone (GH) receptor activation based on a number of physicochemical techniques, and documents insights gained into the means used by the activated GH receptor to control the expression of genes regulating growth and metabolism. These findings are related to disorders of short stature, and the therapeutic consequences are summarized.

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“…Suppression of IGF-I was observed over 10 weeks of dosing. In cynomolgus monkeys, ATL-1103 given twice weekly over a period of 6 weeks suppressed IGF-I levels by 35% in comparison to placebo [178]. In a Phase I clinical trial with 36 healthy adult male subjects, the drug showed a significant decrease of IGF-I as well as a significant reduction in GH-binding protein (GHBP) by 16% after 3 weeks (press release, Antisense Therapeutics).…”

Section: Antisense Drugs 731 Atl-1103mentioning

confidence: 99%