Related Experiment Video
Updated: Sep 29, 2025
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Efficacy of PEGylated ciliary neurotrophic factor superagonist variant in diet-induced obesity mice
Maria Rosaria Battista1, Antonella Grigoletto2, Tommaso Tedeschini2
1IRBM SpA, Pomezia, Rome, Italy.
Abstract:
Ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine able to induce appetite reduction, weight loss and antidiabetic effects. However, its susceptibility to neutralizing anti-CNTF antibodies in patients hampered its use for treatment of human obesity and diabetes. In addition, CNTF has a very short plasma half-life, which limits its use as a therapeutic agent. Solutions, directed to prolong its in vivo effects, vary from the implantation of encapsulated secreting cells to identification of more active variants or chemical modification of the protein itself. PEGylation is a widely used modification for shielding proteins from circulating antibodies and for increasing their plasma half-life. Here, we have selected DH-CNTF, a CNTF variant which has a 40-fold higher affinity for the CNTF receptor α accompanied by an increased activity in cellular assays. The PEGylated DH-CNTF retained the biological activity of native protein in vitro and showed a significant improvement of pharmacokinetic parameters. In an acute model of glucose tolerance, the PEG-DH-CNTF was able to reduce the glycemia in diet-induced obese animals, with a performance equaled by a 10-fold higher dose of DH-CNTF. In addition, the PEGylated DH-CNTF analog demonstrated a more potent weight loss effect than the unmodified protein, opening to the use of CNTF as weight reducing agent with treatment regimens that can better meet patient compliance thanks to reduced dosing schedules.
Insights
Engineered Ciliary neurotrophic factor (CNTF) with PEGylation (PEG-DH-CNTF) shows improved pharmacokinetics and enhanced weight loss and antidiabetic effects in obese animal models. This modified CNTF offers a promising therapeutic strategy for obesity and diabetes treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Ciliary neurotrophic factor (CNTF) exhibits potential for treating obesity and diabetes due to its appetite-reducing, weight-loss, and antidiabetic properties.
- Therapeutic application of native CNTF is limited by neutralizing antibodies and a short plasma half-life.
- Protein modification strategies, such as PEGylation, are employed to enhance therapeutic protein efficacy and duration of action.
Purpose of the Study:
- To develop a modified CNTF variant (DH-CNTF) with enhanced receptor affinity and activity.
- To PEGylate DH-CNTF to improve its pharmacokinetic profile and in vivo efficacy.
- To evaluate the therapeutic potential of PEG-DH-CNTF in diet-induced obese animal models.
Main Methods:
- Selection of a high-affinity CNTF variant (DH-CNTF) with increased cellular activity.
- PEGylation of DH-CNTF to create PEG-DH-CNTF.
- In vitro assessment of PEG-DH-CNTF's biological activity.
- Evaluation of PEG-DH-CNTF's pharmacokinetic parameters and its effects on glucose tolerance and weight loss in diet-induced obese mice.
Main Results:
- DH-CNTF demonstrated a 40-fold higher affinity for its receptor and increased activity in cellular assays.
- PEG-DH-CNTF retained the in vitro biological activity of native CNTF and exhibited improved pharmacokinetic parameters.
- PEG-DH-CNTF significantly reduced glycemia in an acute glucose tolerance test in obese mice, comparable to a 10-fold higher dose of DH-CNTF.
- PEG-DH-CNTF induced a more potent weight loss effect than unmodified DH-CNTF.
Conclusions:
- PEGylation of the high-affinity CNTF variant DH-CNTF successfully improved its pharmacokinetic properties while maintaining biological activity.
- PEG-DH-CNTF demonstrates significant therapeutic potential for managing hyperglycemia and promoting weight loss in obese individuals.
- The enhanced properties of PEG-DH-CNTF may allow for reduced dosing schedules, improving patient compliance in obesity and diabetes treatment.
More Related Videos
07:08Using Optical Coherence Tomography and Optokinetic Response As Structural and Functional Visual System Readouts in Mice and Rats
Published on: January 10, 2019
09:10Palatable Western-style Cafeteria Diet as a Reliable Method for Modeling Diet-induced Obesity in Rodents
Published on: November 1, 2019