Tag Archives: NMJ

/** */

Condition Green

As many of you might already know, I was the late-stage PALS mentioned in the recent Genervon press release. I got interested in this drug some time ago, did some research on it and wrote a blog post about it. I had contacted the company, Genervon, to get information for my post. Thereafter, a dialogue was maintained regarding clinical trial status and future development plans. Being that I am a late stage PALS and still extremely active in awareness, advocacy, and science, they agreed to my request for compassionate use. It was another 9 months going through the process of authorization (mostly because my local hospital had never done anything like this before and together we created a new protocol).

During that time the Phase 2A results came out and I was given access to some of the data. Those, combined with my own experience, gave me the satisfaction that this drug was safe and quite likely effective. I share the concerns about trial size, but like all PALS am concerned for the time required to go through the usual phases of clinical trials. The clinical trial program actually has four parts:

  • Phase 1 – single dose usually in healthy subjects for gauging safety
  • Phase 2 – use in actual patients looking at safety and initial efficacy
  • Phase 3 – larger patient population with different doses, efficacy and SAEs
  • Phase 4 – market surveillance for adverse events

Not only does it take time to fully enroll and execute a large clinical trial but it takes even more time to secure the funding necessary to begin each phase. This is especially true in this current era of venture capital avoiding biotech investment.

I have helped launch other initiatives to get PALS access to experimental treatments. It is critical that patients get more than one or perhaps two chances at early access to treatment while they are newly diagnosed. Drugs that are possibly effective must be made broadly available to patients who are facing otherwise-certain death. Based on the safety and the indication of efficacy in GM6 (mainly borne of my personal experience), I got behind the effort to seek what FDA calls Accelerated Approval so that many more PALS can try it and see where it takes us. Accelerated Approval requires full data surveillance for efficacy, not just serious adverse events (SAEs). The efficacy data determines whether final approval is made. Basically, Accelerated Approval is like a Phase 3 where patients/insurance pay for participation. I believe all PALS would gladly participate in such a program.

If the wider data don’t support the continued use of GM6 I will be the first to admit it. But right now I believe GM6 has the capability to effectively treat ALS in a way no previous drug ever has. And I want to get that opportunity as quickly as possible to as many PALS as possible.

After publishing the press release and posting it on social media and online forums, another PALS started a petition to the FDA to demonstrate the support in the ALS Community for this Accelerated Approval. I would like to urge all who are concerned about ALS – PALS/CALS/Friends – to sign this petition and share it among your social circles. At that link you can sign the petition and post comments to be included with your name. You can also find links to email Senators who oversee FDA and proposed text for those messages.

It is imperative that the comments left on the petition signatures be respectful. FDA isn’t the enemy. They really would like nothing better than to approve a treatment for ALS but need the data to support it. I think we have the data because even though the population was small, the slope of decline as measured by the ALSFRS-R was reduced significantly during the short treatment window. Also, certain biomarker candidates were tracked and correlated with progression. Nevertheless, FDA has to be very careful with the precedent it sets so we as patients must be partners with them in these decisions.

My own experience with GM6 has been positive. The worst part of the entire project was getting the PICC line and the lumbar punctures for CSF samples to make biomarker measurements. I experienced absolutely no adverse events related to the drug. Insofar as benefits, I must admit that the small gains in function noted in the press release are most likely due to surviving neurons branching out new axon terminals to cover the neuromuscular junctions (NMJs) abandoned by the dying motor neurons affected by ALS. GM6 will NOT regrow dead motor neurons. However, it does induce healing in injured ones. In my case, I probably don’t have many injured motor neurons – most of mine are gone. But people who are more recently diagnosed have a higher chance of regaining some lost function in addition to stopping progression.

Based on the information I have seen and my own positive experience, along with the considerable (at best) delay in commencing a larger Phase 2 or 3 trial, I think GM6 deserves Accelerated Approval. I also think this could set a beneficial precedent for future drugs which show similar safety and efficacy signals in early trials. Hence my hope for GM6 getting into the larger population of PALS.

/** */

Carpe Fragments

In the developing embryo, motor neurons develop and nearly half preferentially die prior to birth (Henderson, et al., 1997, “Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons”). As shown in Forger, et al., 2001 (“Blockade of Endogenous Neurotrophic Factors Prevents the Androgenic Rescue of Rat Spinal Motoneurons”), loss of muscular targets also leads to post-natal motor neuron degeneration. Post-natal mice engineered to have degenerated muscle spindles exhibit ataxia and resting tremors, indicating a decrease in proprioception due to loss of sensory-motor synapses (Frank, et al., 2002, “Muscle Spindle-Derived Neurotrophin 3 Regulates Synaptic Connectivity between Muscle Sensory and Motor Neurons”).

One interesting factor seems to suggest a link with testosterone in preserving motor neurons, which could be a possible explanation for the statistically higher numbers of men affected in middle-age or above, and that of women in post-menopause, when hormone levels experience radical shift. Indeed, Cilliary Neurotrophic Factor, a potent motor neuron trophic factor, is regulated by gonadal hormones (Forger, et al., 1998, “Ciliary Neurotrophic Factor Receptor in Spinal Motoneurons is Regulated by Gonadal Hormones”).

Leaving aside the question of hormone levels, there is much evidence that muscle-derived neurotrophic factors are necessary for the health and survival of the motor neurons. One in particular, Motoneuronotrophic Factor 1 (MNTF1), appears essential to this critical process. Experiments in Wobbler mice show that motor neuron disease increases as MNTF1 levels decrease (http://www.ncbi.nlm.nih.gov/pubmed/10453487). MNTF1 was first described in the early 90s, and the human form was successfully cloned as an artificial protein. Various fragments were extracted and shown to have neurotrophic effect.

Two overlapping domains of a 33 amino acid fragment of MNTF1, dubbed the Fred and Wilma domains, are sufficient to stimulate motor neuroprotection in a manner similar to the whole 33 amino acid MNTF1 fragment. The Fred domain is sufficient to direct selective reinnervation of muscle targets by motor neurons in vivo in a manner similar to the 33 amino acid MNTF1 fragment. A recombinant protein containing the Fred domain maintained motoneuron viability, increased neurite outgrowth, reduced motoneuron cell death/apoptosis and supported the growth and spreading of motoneurons into giant, active neurons with extended growth cone-containing axons.

For those curious about the amino acids in each domain, please refer to the image below:

Genervon has patented these fragments and is using them in a Phase 2-A clinical trial in ALS.

From the above it is quite possible that at least some forms of ALS are caused by a sort of a muscular dystrophy (not to be confused with the distinct condition by that name). It therefore stands to reason that there is reason for hope that some will benefit. The standard caveat of basic and preclinical research often not translating to human trials obviously applies. However, we are entering an exciting time where extremely potent shots are being taken at more fundamental aspects of ALS. One or a combination seem likely to have the effect we have been waiting for.

/** */

Old Tricks

Something very intriguing came in over the weekend from PLoSONE. It was a study comparing neuromuscular junctions between age and ALS. It turns out that the same muscles susceptible to denervation in ALS are likewise susceptible to denervation with age. Autonomic muscles (those that act without your conscious input) and muscles innervated directly from the brain (eg your eyes and certain facial muscles) are extraordinarily resistant to age- and ALS-related denervation. Something that struck me was the finding that TDP43 was mislocalized in aged motor neurons very similarly to ALS motor neurons. TDP43 is normally found in the nucleus but in ALS it is found in the cytoplasm where it is cleaved by caspases and a 25 kilodalton fragment aggregates in a form that apparently gains a toxic function.

TDP43 mislocalization has also been found by the symptomatic phase in the SOD1 mouse model (although earlier and more recent reports are somewhat contradictory on this point). Another protein found upregulated in the SOD1 mouse is CRMP4a, a subprotien of the CRMP family. CRMP4 is normally involved in learning, neurite outgrowth, and building functional circuitry within the brain. However, the Duplan, et al., 2010 study referenced above found upregulation or overexpression of CRMP4a is deadly specific to motor neurons. In the subject study of this post, Valdez, et al., 2012, CRMP4a was also found upregulated in the same types of motor neurons of normally-aged mice as those which degenerate in ALS mice. CRMPs are known to change due to age.

Inflammation is present in all neurodegenerative diseases. One of the primary drivers of ALS is thought to be neuroinflammation. Multiple animal models of ALS, including data in humans, show neuroinflammation. As the subject study shows, TDP43 and CRMP4 is upregulated in both aging and ALS. Taking one step further, aging and ALS have another thing in common: Inflammation.