Anavex Life Sciences Corp (AVXL)

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What is COMT? Why is COMT important for the AVXL 2-72 AD and PDD clinical trials? The COMT gene and/or variants thereof play a role in Alzheimer's and Parkinson's. Here's a number of articles about that including articles about AVXL 2-73 and COMT variants.

1. https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/

Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

Researchers have found that Parkinson’s patients whose cognitive ability is intact, but who have a specific genetic variant, have significantly less gray matter in the regions of their brain that are related to dementia.

The study with that finding, “Reduced gray matter volume in cognitively preserved COMT 158Val/Val Parkinson’s disease patients and its association with cognitive decline,” was published in Brain Imaging and Behavior.

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/

2. https://www.ptcommunity.com/wire/anavex-life-sciences-presents-new-data-identifying-treatment-response-biomarkers-alzheimer-s

Several genetic variants that impacted response to ANAVEX®2-73 were identified in the study analysis including the Sigma-1 receptor (SIGMAR1), the target for ANAVEX®2-73, and the Catechol-O-methyltransferase (COMT) gene, produced by nerve cells and involved in memory function. Results showed that study participants with SIGMAR1 (rs1800866) or COMT (rs113895332/rs61143203) variants were less likely to benefit from treatment with ANAVEX®2-73. In the study population, when participants with these variants (approximately 20 percent) were excluded, the remaining study participants (approximately 80 percent) showed improved scores on gold-standard tests of cognition (MMSE) and activities of daily living (ADCS-ADL) (p<0.05).

Including participants with milder disease (baseline MMSE ≥20) and excluding those with a SIGMAR1 variant resulted in an average improvement of +1.7 MMSE and +3.9 ADCS-ADL at week 57 compared to baseline. The additional exclusion of participants with the COMT variant resulted in a score improvement of +2.0 MMSE and +4.9 ADCS-ADL at week 57 compared to baseline.

3. https://www.neurologylive.com/conferences/aaic-2018/harald-hampel-md-phd-ma-msc-genomic-analysis-of-anavex-273-in-alzheimer-disease-study

Anavex identified several genetic variants that impacted the response to ANAVEX 2-73, a selective sigma-1 receptor (SIGMAR1) agonist, which include SIGMAR1, ANAVEX 2-73’s target, and the Catechol-O-methyltransferase (COMT), a gene involved in memory function.

Harald Hampel, MD, PhD, MA, MSc: Genomic Analysis of ANAVEX 2-73 in Alzheimer Disease Study

4. https://ghr.nlm.nih.gov/gene/COMT

What is COMT?

Catechol-O-Methyltransferase (COMT) is one of several enzymes that degrade dopamine, epinephrine, and norepinephrine. COMT breaks down dopamine mostly in the part of the brain responsible for higher cognitive and executive function (prefrontal cortex) [1].

The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones.

In the brain, catechol-O-methyltransferase helps break down certain chemical messengers called neurotransmitters. These chemicals conduct signals from one nerve cell to another. Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966542/

Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans.

6. https://pubmed.ncbi.nlm.nih.gov/29439855/

Catechol-O-methyltransferase (COMT) Genetic Variants Are Associated With Cognitive Decline in Patients With Parkinson's Disease

7. https://parkinsonsnewstoday.com/2019/01/11/genetic-variant-predetermine-cognitive-decline-parkinsons/

Genetic Variant Predetermines Risk of Cognitive Decline in Parkinson’s, Research Suggests

Several mutations in the COMT gene have been associated with the risk of developing Parkinson’s disease. This gene provides instructions for making catechol-O-methyltransferase (COMT), an enzyme that helps break down certain chemical messengers like dopamine.

The most common alteration in the DNA sequence that makes up the COMT gene is the Val158Met mutation in which a valine (Val) is replaced by a methionine (Met) at position 158. Val and Met are both amino acids, also known as the protein’s building blocks.
...
The Val158Met mutation in the COMT gene has been associated with an increased risk of cognitive decline in Parkinson’s disease, particularly in people with greater COMT activity. When this happens, there is too much neurotransmitter degradation, thus leading to reduced levels of dopamine and affecting basic brain functions such as motor coordination and memory.

Evidence suggests a correlation between cognitive impairment, one of Parkinson’s non-motor features, and reduced gray matter volume.
...

A Spanish team of researchers used magnetic resonance imaging (MRI), a non-invasive imaging technology, to investigate a possible structural brain compromise in Parkinson’s patients with highly active COMT activity that could explain their increased risk for subsequent cognitive impairment.

The study included 120 newly diagnosed Parkinson’s patients with normal cognition (who were not previously treated for the disease) and 48 healthy controls from the Parkinson’s Progression Markers Initiative database.

Results showed that there was a widespread, significant reduction in cerebral gray matter volume in patients with the Val/Val genotype. They observed alterations in the fronto-subcortical and posterior-cortical brain regions, where motor and cognitive functions originate.

8. https://pubmed.ncbi.nlm.nih.gov/22483294/

...Catechol-O-mehyltransferase (COMT) is surfacing with a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. COMT gene regulates dopamine levels in the prefrontal cortex which are involved in working memory and executive functioning. Impaired executive functioning is reported in a subgroup of AD patients and is associated with a more severe disorder, a more rapid disease progression and a shorter survival. .......... COMT inhibitors, that are adjunctive drugs in Parkinson's disease treatment, lower homocysteine levels and improve executive memory processes in normal subjects. A preliminary study, which needs replication, demonstrates that COMT inhibitors block beta-amyloid fibrils in vitro. Taken together, these findings suggest that research should focus on the role of COMT in AD pathogenesis and on the feasibility of targeting COMT activity in AD treatment.