Anxiety Regulation Through Lynx2-mediated Cholinergic Modulation

Background

The protein product of the lynx2 gene is expressed in several areas of the brain but is highly concentrated in the basolateral amygdala – a central regulator of the human stress response and anxiety. At the cellular level, perturbations in the function of synapses regulated by the neurotransmitter acetylcholine have been associated with abnormal neuronal excitability in the amygdala. The nicotinic acetylcholine receptor (nAchR) has been implicated in regulating excitability and network function in the amygdala. Under physiological conditions, lynx2 binds to nAchRs and acts as a “molecular brake” by weakening their response to normal synaptic input. In lynx2-deficient mice, synaptic responses in the amygdala are highly sensitive to nicotine, suggesting that the brake normally imposed by lynx2 on nAchR function has been removed. Furthermore, lynx2-deficient mice exhibit anxiety behaviors, and enhanced release of the neurotransmitter GABA, which is a target of several commercially available anxiolytics, including benzodiazepines.

The Lehigh inventors have demonstrated that blocking nAchRs with pharmacological antagonists such as macamylamine can restore synaptic plasticity and anxiety behaviors such as learned fear deficits and social interaction deficits. This data is the first to indicate a causal relationship between cholinergic transmission and anxiety via a lynx2- dependent mechanism. The data also suggests that pharmacological antagonists to the nAchR could ameliorate anxiety behaviors caused by impairments in lynx2 expression and/or function.

Competitive Advantages

Current available treatments for anxiety disorders provide only short-term relief, while the proposed invention could potentially provide longer-lasting relief

Pharmacological cholinergic modulators can easily be altered by medicinal chemical means to achieve tolerability in humans

The proposed therapy could have a broader impact on other stress-related disorders such as PTSD and social disorders

Several cholinergic modulators have already demonstrated positive safety and tolerability results in clinical trials for major depressive disorder.

Lehigh University Tech ID # 100115-01

Market

The Anxiety and Depression Association of America has reported that ~40 million people in the U.S. suffer from anxiety disorders, and the cost of treating these patients is $42 billion each year. Benzodiazepines are a highly used pharmacological therapy that only provide short-term relief and do not modify the root cause of the disease.  Therefore, novel therapeutic interventions that slow or halt disease progression with long-acting duration remain an unmet medical need. The overall anxiety disorders therapeutics market is forecasted to grow at a CAGR of 6.3% over the next seven years, to reach $5.6 billion by 2017. This steady growth is primarily attributed to only one recent product launch, as well as an increase in disease awareness and the early-stage development of alternative treatment options

App Type Country Serial No. Patent No. File Date Issued Date Expire Date
Provisional [PR] United States 62/237,969 10/6/2015    
Category(s):
Therapeutics
Biology
For Information, Contact:
Thomas Meischeid
Interim Director
Lehigh University
tjm5@lehigh.edu
Inventors:
Julie Miwa
Huaixing Wang
Kristin Anderson
Keywords: