PASADENA, CA, USA I September 22, 2015 I Researchers and clinicians have long recognized that ALS is a heterogeneous neurodegenerative disease. Recently scientists are beginning to understand why that is the case. One of the major pathological features observed in post-mortem tissue from patients with ALS is cytoplasmic neuronal aggregations formed by TDP-43 DNA binding Protein.

Dr. Virginia Lee of University of Pennsylvania School of Medicine has provided critical evidence that the aggregation of brain proteins is a common mechanistic theme in diverse neurodegenerative diseases, including AD, PD, FTD, ALS and related disorders. In an estimated 97 percent of people with ALS/MND and in 45 percent of those with Alzheimer/FTD, the pathological protein TDP-43 aggregated inside brain or nerve cells.

Dr. Inoue of Kyoto University demonstrated that the neurites in purified iPSC-derived motor neurons from ALS patients are shorter than from healthy subjects. TDP-43 spreads out from the nucleus to the cytoplasm, forms aggregation and becomes toxic, causing the death of motor neurons. As TDP-43 mRNA levels decreased, the death of neurons was prevented and the previously short projection of nerves became longer. Therefore, a slowing of ALS disease progression is expected.

Dr. Philip Wong of Johns Hopkins University published in Science 7 August 2015 that TDP-43 is normally responsible for keeping unwanted stretches of the genetic material RNA, called cryptic exons, from being used by nerve cells to make proteins. When TDP-43 forms aggregates inside those cells, it malfunctions, lifting the brakes on cryptic exons which then cause the making of random defective proteins resulting in a different cascade of events that kills brain or spinal cord cells – the heterogeneous pathology of ALS.

Human Clinical data tracking TDP-43

Genervon Biopharmaceuticals has spent over 20 years discovering and developing novel and innovative embryonic stage endogenous multiple-target master regulator peptide drugs to restore homeostasis in patients with neurological and neurodegenerative diseases. Classical single target drugs are mono-directional: agonist or antagonist. Genervon has proven its hypothesis that the endogenous signaling master regulator GM604 can restore health of neurons by bringing homeostasis when protein expressions are either above or below the normal range.

The results of Genervon’s Phase 2A clinical trial of GM604 in ALS patients indicated that GM604 has the ability to modulate multiple protein biomarkers, including the above normal TDP-43 back to their normal ranges, thus restoring homeostasis. The percent change of TDP-43 by GM604 in the advanced patient for compassionate use was -63% in 12 weeks. The mean of the percent change in TDP-43 of the treated group in Phase 2A group was -34%, and the mean of percent change in the placebo patient group was +6%. GM604 significantly reduced the slope of plasma TDP-43 concentration at 12 weeks when compared with placebo (p=0.0078).

Genervon believes that GM604 reduced the clumping of TDP-43 in treated patients and thus reduced the formation of random protein aggregates and brings clinical improvements in the heterogeneous ALS patient population.

Professional Athletes with ALS

A number of rugby athletes who are recently being treated by GM604 have been exposed to pesticides applied to playing fields. Some of them have the habit of licking their fingers to get a better grip of the ball. In the absence of functioning TDP-43, toxic pesticides and harmful chemicals as random segments of RNA may inject themselves during protein formation to create faulty/misfolded proteins within the cell causing the neural cells to die. GM604 can modulate TDP-43 and stop the formation of random misfolded proteins by toxins.

SOURCE: Genervon