Anavex Life Sciences Corp (AVXL)

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A Second Blarcamesine MOA for HSP

Some time ago I posted my evidence-based conjecture that blarcamesine very likely will be a successful therapy for at least some forms, probably most, of hereditary spastic paraplegia (HSP), a rare disease where motor neurons, controlling body muscles, most prominently those controlling gait, in the legs, remain hyper-exited; constantly firing.

I have a genomically-confirmed case of HSP, with one of less severe genotypes. Severe cases become evident in childhood and muscles across the entire body are lethally spastic. Several dozen genotypes have now been identified, and mine is one of the less severe. Mine was primarily a middle-age on-set type. My legs stiffened in my 50s. Today, to walk I need the assistance of a walker; can’t go up or down staircases. But I can drive with complete safety and function. Wonderfully, there is no pain; just a confounding gait-inhibiting spasticity. (Well, it also caused a neurogenic bladder, so I surgically had to have created a suprapubic cystostomy, where I now have to contend with a suprapubic catheter.)

In severe cases (which it appears I will never attain), a fluid-filled sac containing baclofen is surgically placed in the spinal column, where the drug slowly perfuses into the long motor neurons extending to the adductor and other muscles of the leg, where the drug inhibits the continual firing of those nerves. Periodically, the sac is injected with make-up baclofen. A less than satisfactory treatment for severe cases of HSP. Thankfully, I have no prospect of needing the baclofen pump.

One understood mechanism of some or most forms of HSP is a deficiency of gamma-amino buytric acid, GABA, within neurons. GABA is an inhibiting neurotransmitter; keeping neurons from over-firing when exited by a nerve impulse. Nerves lacking sufficient GABA fire frequently or constantly; hence the spasticity of many or most forms of HSP.

Of course, the clinical trial of blarcamesine with girls with Rett syndrome revealed markedly increased, even restorative concentrations of GABA in their neurons. GABA-deficient Rett syndrome neurons account for the poor motor, muscle control of these afflicted girls. Blarcamesine’s ability to restore functional concentrations of GABA for them accounts, at least in one manner, for how the drug will be a useful Rett therapy.

From that clinical evidence, in real humans, I projected that blarcamesine would likewise be a successful treatment for GABA-deficient cases of HSP; for me, even. Eager to give it a try.

But, not all cases of HSP are solely GABA-deficiency diseases. It has just been discovered that dysfunctional calcium transport at the endoplasmic reticulum (ER) is also a cause of some or many forms of HSP. Very likely, both pathological mechanisms are involved.

The new research is here:
https://www.eurekalert.org/news-releases/983999

It’s a long and detailed report. “The results obtained indicate a new mechanism whereby the structure of the endoplasmic reticulum controls the synaptic function, and suggest a possible pathway by which it could cause hereditary spastic paraplegia.” In the simplest terms, restoration of calcium transport related to the endoplasmic reticulum should be profoundly therapeutic. Of course, blarcamesine activates the sigma-1 receptor protein, which then profoundly facilitates normalized calcium transport to and within the endoplasmic reticulum.

Now the form of HSP described in this paper is not one of the more common GABA deficiency forms. But, it now appears that two mechanisms of action (MOAs) of blarcamesine, both GABA synthesis and calcium transport at the ER, will be therapeutic for the disease.

HSP will be another human disease for which blarcamesine can yield safe, effective therapy.