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Publications 2013

A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.

By Bianchi, Elisabetta; Carrington, Paul E.; Ingallinella, Paolo; Finotto, Marco; Santoprete, Alessia; Petrov, Aleksandr; Eiermann, George; Kosinski, Jennifer; Marsh, Donald J.; Pocai, Alessandro; et al
From Bioorganic & Medicinal Chemistry (2013), 21(22), 7064-7073. Language: English, Database: CAPLUS, DOI:10.1016/j.bmc.2013.09.016

Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addn. to increasing glucose-dependent insulin secretion, they also cause wt. loss. Oxyntomodulin (OXM), a natural peptide with sequence homol. to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clin. utility is limited by a short circulatory half-life due to rapid renal clearance and degrdn. by dipeptidyl peptidase IV (DPP-IV). Here, the authors describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high mol. wt. polyethylene glycol (PEG) (‘PEGylation’). PEG-OXM exerts an anti-hyperglycemic effect in diet-induced obese (DIO) mice in a glucose-dependent manner, with a maximally efficacious dose of 0.1 mg/kg, and reduces food intake and body wt. with a minimally efficacious dose of 1 mg/kg. If this pharmacol. is recapitulated in patients with type 2 diabetes, these results indicate PEG-OXM as a potential novel once-weekly GLP-1 mimetic with both glucose-lowering activity and wt. loss efficacy.

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A transgenic minipig model of Huntington’s Disease

By Baxa Monika; Macakova Monika; Hruska-Plochan Marian; Juhas Stefan; Pavlok Antonin; Juhasova Jana; Klima Jiri; Motlik Jan; Vodicka Petr; Miyanohara Atsushi; et al
From Journal of Huntington’s disease (2013), 2(1), 47-68, Language: English, Database: MEDLINE

Some promising treatments for Huntington’s disease (HD) may require pre-clinical testing in large animals. Minipig is a suitable species because of its large gyrencephalic brain and long lifespan. OBJECTIVE: To generate HD transgenic (TgHD) minipigs encoding huntingtin (HTT)1-548 under the control of human HTT promoter. METHODS: Transgenesis was achieved by lentiviral infection of porcine embryos. PCR assessment of gene transfer, observations of behavior, and postmortem biochemical and immunohistochemical studies were conducted. RESULTS: One copy of the human HTT transgene encoding 124 glutamines integrated into chromosome 1 q24-q25 and successful germ line transmission occurred through successive generations (F0, F1, F2 and F3 generations). No developmental or gross motor deficits were noted up to 40 months of age. Mutant HTT mRNA and protein fragment were detected in brain and peripheral tissues. No aggregate formation in brain up to 16 months was seen by AGERA and filter retardation or by immunostaining. DARPP32 labeling in WT and TgHD minipig neostriatum was patchy. Analysis of 16 month old sibling pairs showed reduced intensity of DARPP32 immunoreactivity in neostriatal TgHD neurons compared to those of WT. Compared to WT, TgHD boars by one year had reduced fertility and fewer spermatozoa per ejaculate. In vitro analysis revealed a significant decline in the number of WT minipig oocytes penetrated by TgHD spermatozoa. CONCLUSIONS: The findings demonstrate successful establishment of a transgenic model of HD in minipig that should be valuable for testing long term safety of HD therapeutics. The emergence of HD-like phenotypes in the TgHD minipigs will require more study.

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Further molecular characterisation of the OVT73 transgenic sheep model of Huntington’s disease identifies cortical aggregates.

By Reid Suzanne J; Patassini Stefano; Handley Renee R; Waldvogel Henry J; Faull Richard L M; Snell Russell G; Rudiger Skye R; McLaughlan Clive J; Bawden C Simon; Osmand Alex; et al
From Journal of Huntington’s disease (2013), 2(3), 279-95, Language: English, Database: MEDLINE

Huntington’s disease is a neurodegenerative disorder, typically with clinical manifestations in adult years, caused by an expanded polyglutamine-coding repeat in HTT. There are no treatments that delay or prevent the onset or progression of this devastating disease. OBJECTIVE AND METHODS: In order to study its pre-symptomatic molecular progression and provide a large mammalian model for determining natural history of the disease and for therapeutic testing, we generated and previously reported on lines of transgenic sheep carrying a full length human HTT cDNA transgene, with expression driven by a minimal HTT promoter. We report here further characterization of our preferred line, OVT73. RESULTS: This line reliably expresses the expanded human huntingtin protein at modest, but readily detectable levels throughout the brain, including the striatum and cortex. Transmission of the 73 unit glutamine coding repeat was relatively stable over three generations. At the first time-point of a longitudinal study, animals sacrificed at 6 months (7 transgenic, 7 control) showed reduced striatum GABAA α1 receptor, and globus pallidus leu-enkephalin immunoreactivity. Two of three 18 month old animals sacrificed revealed cortical neuropil aggregates. Furthermore, neuronal intranuclear inclusions were identified in the piriform cortex of a single 36 month old animal in addition to cortical neuropil aggregates. CONCLUSIONS: Taken together, these data indicate that the OVT73 transgenic sheep line will progressively reveal early HD pathology and allow therapeutic testing over a period of time relevant to human patients.

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