GM604 (also known as GM6) is a potential treatment for amyotrophic lateral sclerosis (ALS), being developed by Genervon. According to the stated purpose of a Phase 2A clinical trial, GM604 is an “endogenous human embryonic stage neural regulatory and signaling peptide that controls the development, monitoring, and correction of the human nervous system.”

ALS is an incurable disease that leads to the degeneration of motor neurons in the brain (upper motor neurons) and spinal cord (lower motor neurons). As the disease progresses, motor neurons are no longer able to send messages to the muscles, leading to atrophy and increased muscle weakness.

It is thought that GM604 may prolong motor neuron survival in ALS patients, by slowing their degeneration.

How GM604 works

GM604 affects more than 4,000 genes and modulates at least eight pathways involving up to 22 biologic functions.

GM604:

  • reduces damage caused by free radicals inhibiting cell death;
  • protects nerve cells by activating PIP3 kinase, a key signaling component frequently mutated in human cancers;
  • reduces neuronal cell death by inhibiting Bax, the activity of which promotes the spread of cancer.
  • Activates Akt protein kinase to suppress SOD1 (superoxide dismutase 1) gene expression, which causes ALS;
  • normalizes hypoxic response (how different cells and tumors react to oxygen shortage) to prevent ALS degeneration;
  • increases the capability to repair DNA inhibiting programmed cell death, and;
  • stimulates axonal transport, delaying the onset of ALS.

Genervon researchers suggest a triple mechanism of action, where GM604 could prolong motor neuron survival in people with ALS. First, GM604 may reduce SOD1 expression and block the accumulation of SOD1 aggregates in motor neurons. Second, it may reduce mitochondrial gene expression and potentially mitochondrial abundance, disrupting the mitochondrial death path. Third, it may activate developmental/mitotic pathways, which may promote cellular repair and the formation of new axons and nerve cell projections.

GM604 research

GM604 has been shown to be effective in disease modification in animal models of ALS with mutated SOD1, leading to an improved clinical score in SOD1 mice. GM604 delayed the onset of ALS symptoms by 27 percent, extended life by 30 percent, and delayed the median clinical score deterioration time by 41 percent.

In a wobbler mice model for motoneuron diseases such as ALS, GM604 increased life span by 500 percent (six fold from 7-14 weeks to 55-65 weeks) and increased motor neurons preservation by 160 percent (2.6 fold)

In vitro studies have shown that GM604 provides neuroprotection against soluble inflammatory factors from the cerebrospinal fluid of people with ALS by 175 percent.

Results from a Phase 2A randomized double-blind placebo-controlled study in ALS (NCT01854294) were published. Primary objectives were the efficacy, as measured by percent change in biomarker in the cerebrospinal fluid at 12 weeks, safety, as measured by the frequency and severity of adverse events, changes in vital signs and clinical laboratory values different from the biomarker in the cerebrospinal fluid, and tolerability as measured by the ability to complete the first two weeks of active treatment in the study.

The results also showed favorable changes in ALS biomarkers and improved clinical and functional measures in Revised ALS Functional Rating Scale (ALSFRS-R) and Forced Vital Capacity (FVC), suggesting that GM604 has different ways of action:

This data encourages and supports GM604 as an ALS treatment. A Phase 3 study is being planned during 2017, but there are no enrollment details yet.

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