University Researchers have developed a proprietary approach that addresses the treatment of Alzheimer’s Disease (AD) and other neurological disorders through a mechanism of action differentiated from current therapies.
The approach employs a series of promising GLP-1 analogues with lead compounds that cross the blood-brain barrier and activate neuronal incretin receptors.
· Alzheimer’s disease (AD) is a chronic, degenerative disease of the brain for which there arecurrently no drugs available for its prevention or cure. Recent estimates suggest there are currently 44 million people worldwide affected by the disease with one new case being diagnosed every 3.2 seconds.
· A recent study published in the medical journal of the American Academy of Neurology has pinned AD as the 3rd leading cause of death in the U.S. and the global cost of the disease is estimated to be 1% of the world’s GDP ($605 billion).
· The incidence of AD and other forms of dementia is expected to continue to grow significantly with an estimated 100 million people impacted worldwide by 2050. As such, there is a clear need for the development of disease modifying drugs capable of prevention, delay of onset, slowing of progression or improving the symptoms of this devastating disease.
· Recently, type 2 diabetes (T2D) has been identified as a risk factor for AD, most likely linked to an impairment of insulin signalling in the brain. As a result, a promising strategy to prevent AD could be to normalize insulin signalling in the brain, however, treatment of AD with insulin is not recommended due to the likely adverse effects of hyperinsulinaemia resulting in a hypoglycaemic effect in patients with normal blood glucose levels.
· Parallel pathways to that of insulin exist and include the incretin hormone glucagon-like peptide (GLP-1).
· GLP-1 is an endogenous 30 amino acid gastrointestinal hormone and agonists of the GLP-1 receptor, including exendin-4 (Exenatide, Byetta®) and liraglutide (Victoza®) are currently approved and on the market for treatment of T2D.
· In addition to its peripheral receptors, GLP-1 has receptors expressed in CNS neurons and has been shown to act as a growth factor in the brain inducing neurite outgrowth and protecting against oxidative injury in cultured neuronal cells.
· Treatment for AD is currently limited to four drugs from two different classes (cholinesterase inhibitors and NMDA receptor antagonists). Clearly, there is a need for the development of new treatments with novel mechanisms of action possessing disease modifying abilities to combat this devastating disease and the increasing associated burden to society.
Preliminary research has shown these analogues to act as neuroprotective agents enhancing and protecting neuronal transmission and in vivo studies in chronic disease models for AD have demonstrated lead compounds to protect from the effects of beta-amyloid build up. These results indicate that such novel incretin analogues possess utility for the treatment and prophylaxis of AD.
· Data has shown lead compounds; eg. Liraglutide (Victoza®); (Val8)GLP-1 and related molecules, to have clear effects in improving symptoms in a transgenic mouse model of AD.
· Molecules readily cross the blood brain barrier, protect and improve memory formation, as well as protect and enhance synaptic transmission in the brain.
· Two key hallmarks of Alzheimer's disease, amyloid plaque formation and inflammation, are much reduced (down to 50%).
· Neuro-neogenesis is increased, suggesting lead compounds could help repair already damaged areas in the brain.
· Analogues have been shown to protect against excitotoxic cell death and oxidative injury in stroke models as well as in cultured neuronal cells.
· Recent studies have demonstrated that pre-treatment with GLP-1 analogues is effective at reversing the beta amyloid induced suppression of L-LTP (late phase LTP) and impairment of cognitive function.
· In vivo studies with a once daily administration of drug have shown that these analogues do not adversely affect blood glucose levels of non-diabetic mice.
Kelly, P., McClean, P. L., Ackermann, M., Konerding, M. A., Holscher, C & Mitchell, C. A. (2015) Restoration of cerebral and systemic microvascular architecture in APP/PS1 transgenic mice following treatment with Liraglutide™. Microcirculation. 22, 2, p. 133-145 13 p.
McClean, P.L, C. Holscher. (2014) Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology, 2014 Jan; 76 Pt A:57-67.
McClean, P.L, Parthsarathy, V., Faivre, E., and C. Holscher. (2011) The diabetes drug Liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. Journal of Neuroscience. 31, 17, p. 6587-6594.
Ulster University is looking for a potential partner or collaborator to progress this technology. An exclusive licensing of Ulster’s U140B technology provides an opportunity to enhance a licensor’s existing intellectual property pipeline or competitive positioning of this emerging technology.
In addition, inventors of this technology are able to provide valuable know-how in order to assist in its successful commercialisation.
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