Anavex Life Sciences Corp (AVXL)

[MycroftHolmes]

Re: Sigma Receptor & Autism

I have a question I would like to ask you.
There has been some speculation on this MB whether 2-73 or even 3-71 could improve the lives of people with autism. Since Rett disease is related to autism, I was wondering. Do you think/expect that if 2-73 or even 3-71 will be effective in Rett kids it will also be for kids/adults with autism?

My son has autism so we kinda hoping it would of course.

An excellent question, I commend you on your diligence.

There is a mounting pile of evidence that cognitive disorders with different causes follow a similar path of cellular stress:

A possible therapeutic mechanism for sigma-1 receptor agonists in neuropsychiatric diseases.

Stimuli such as oxidative stress, inflammation, disturbances in Ca2þ homeostasis, and enhanced expression of normal and/or folding-defective proteins may lead to the accumulation of unfolded proteins, a condition referred to as ER stress, and, ultimately, to the development of neuropsychiatric diseases.

Cognitive impairment is shown in patients with a number of neuropsychiatric diseases including schizophrenia, major depressive disorder (MDD), bipolar disorder, generalized anxiety disorder (GAD), panic disorder, post-traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), post-stroke depression, and delirium.

In control states, the sigma-1 receptor forms a complex with another ER chaperone, BiP (GRP78). Sigma-1 receptor agonists, such as fluvoxamine, fluoxetine, escitalopram, donepezil, ifenprodil, DHEA (or DHEA-S), and pregnenolone, bind to sigma-1 receptors on the ER, and promote dissociation of the sigma-1 receptor from its complex with BiP (3e5). This dissociated sigma-1 receptor is free to stimulate chaperone activity, resulting in neuroprotection.

SOURCE: Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication

Autism is obviously a more complex case than Rett. Like Cancer and Alzheimer's, there seems to be sub-groups of environmental, biological, and genetic risk factors. But if a person with Autism suffers from cellular imbalance, it does indeed stand to reason that Sigma Receptor targeted drugs might assist.

I asked a related question to a Rett researcher when discussing the upcoming A2-73 trial.

I asked, "if A2-73 is not correcting the underlying genetic/protein malfunction, how much can A2-73 be expected to reduce the symptoms? It is not like it is creating the missing protein."

His response was something along the lines of: Putting High-Grade Oil in a rough running engine will almost always improve the overall function... even if the engine has a bad spark plug

As such, A2-73 & A3-71 would seem excellent candidates for Autism sub-groups that have ER stress, misfolded proteins, mitochondrial dysfunction, Ca++ imbalance, etc. I would follow such a trial with great interest.

But the Sigma Receptor is a flexible and powerful cell modulator so other molecules would also tweak it in very different ways. That is why a Sigma Receptor pipeline is better than any one molecule

Just my opinion but your hope certainly seems to have logical merit.

In the end, we could all benefit from an upgrade to higher-grade oil for the mental gears.

Just my 2 cents,

Cheers

Mycroft