Xenin-25, a promising new preclinical candidate for neurodegenerative diseases (U515)

Tuesday, 25 October 2016

 Preclinical research stemming from Ulster’s Diabetes Research Group has led to the development of a potentially new class of molecules for treatment of neurodegenerative disorders, in particular, Alzheimer’s Disease (AD).

Xenin-25 is a naturally occurring, K-cell derived gut peptide that is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) following a meal.  Stable and longer acting analogues of Xenin-25 have been previously shown to possess potent anti-diabetic activity with no adverse effects and a recent proof of concept study using a transgenic animal model (APP/PS1) for AD demonstrated Ulster’s lead analogue (Xenin25(Lys13)PAL) to have potential as a disease-modifying therapy for neurodegenerative disorders.

Problem Being Solved

·       Alzheimer’s disease (AD) is a chronic, degenerative disease of the brain which currently affects 44 million people worldwide with one new case being diagnosed every 3.2 seconds.  The incidence of disease and other forms of dementia is expected to continue to grow significantly with an estimated 100m people impacted worldwide by 2050. 

·       Treatment for AD is currently limited to five drugs from two different classes (cholinesterase inhibitors and NMDA receptor antagonists), however, existing therapies only provide for symptomatic treatment and there are few drugs in development which offer promise. As such, there is a clear and unmet need for development of new therapies possessing disease-modifying abilities and differentiated mechanisms of action to combat this devastating disease.

·       Biological peptides are one of the most attractive and emerging candidates currently being developed for a host of therapeutic indications due to their numerous advantages over small molecules and/or biologics including high potency, low toxicity, high specificity, low risk of organ accumulation and drug-drug interaction.

·       One such peptide, Xenin-25 has been widely studied for its effects on insulin secretion and glycaemic control. In addition to its anti-diabetic effects, the 25 amino acid peptide has also been shown to impact feeding, suggesting potential behavioural effects and thereby warranting further investigation into its effects in the CNS.

Technology

 Dr. Paula McClean, heading up a team of researchers within Ulster’s Biomedical Sciences Research Institute, has recently carried out proof of concept studies aimed at advancing Ulster’s lead xenin peptide, Xenin25(Lys13)PAL.  

 

Studies conducted to date in an APP/PS1 transgenic mouse model for AD have demonstrated Xenin25(Lys13)PAL to have significant effects on reducing levels of soluble beta amyloid oligomers as well as beta amyloid and congophilic plaque load (which are considered as major histological hallmarks of AD). Xenin25(Lys13)PAL also significantly promoted neuronal cell growth, suggesting it may have clinical utility in the treatment of neurodegenerative diseases such as Alzheimer’s disease.

Benefits/Applications

·       Xenin offers a new mechanistic approach for treatment of neurodegenerative disorders, including AD, based upon an enzyme-resistant and long-acting analogue of the endogenous peptide Xenin-25 (Xenin25(Lys13)PAL).

·       Xenin shows promise in potentiating the action of GIP.  In preliminary studies, using diabetes models, xenin analogues have been shown to potentiate the biological efficacy of the naturally-occurring anti-diabetic hormone GIP which is severely compromised in diabetes. Thus xenin analogues have potential to overcome deficits in GIP activity associated with diabetes, thereby improving overall metabolic control in this disease. There are no reported deficits in GIP action in the context of neurodegenerative disease, therefore xenin may potentiate the actions of native circulating GIP in addition to the effects elicited by exogenous administration of xenin leading to an increase in overall efficacy.

·       Xenin25(Lys13)PAL exhibits superior efficacy to liraglutide (a GLP-1 agonist in clinical development for Alzheimer’s Disease and marketed as Victoza® for type 2 diabetes) in a transgenic mouse model of AD for a number of markers demonstrating clear effects in reducing the histological hallmarks of the disease.

o   Xenin25(Lys13)PAL reduced dense core congophilic plaques by 55% (representing a significant reduction compared to liraglutide).

o   Xenin25(Lys13)PAL significantly increased neuronal growth by 122% (more than a 2.5 fold increase as compared to liraglutide).

o   Xenin25(Lys13)PAL also displayed superiority in reducing the concentration of soluble beta amyloid oligomers, in brain, by 80%. Aggregated beta amyloid oligomers are known to be extremely neurotoxic and have prominent effects on learning and memory, such a significant reduction would be expected to improve neuronal communication in vivo.

Opportunity/Partnership Sought

Further development is needed to better characterize the mechanism of action and underlying biochemical processes of chronic effects of Xenin25(Lys13)PAL in the CNS.  Studies assessing the potential synergistic effects of co-administration of Xenin25(Lys13)PAL and stable forms of GIP are also needed in order to validate the hypothesis that such a combination would indeed yield additive effects. In addition, and as a follow-on to preliminary behavioural studies which suggest trends toward improved learning, a study with greater power could be conducted in order to demonstrate xenin’s potential to induce significant improvements in learning and memory.

 

The University is currently actively seeking a strategic partner to assist in the further development of U515 providing a route to market for the treatment of AD as well as other neurodegenerative disorders such as Parkinson’s disease and multiple sclerosis, amongst others. 

 

For more information please contact:

Dr Oonagh Lynch

Technology Commercialisation Executive

Research & Impact

Tel: +44 (0) 28 9036 6707

Mob: +44 (0) 77 6536 3191

Email:ot.lynch@ulster.ac.uk