Preclinical Results

Common pathological features of ALS & our approach to treatment: ALPHA-602

About 10% of ALS patients have a form of the disease that is inherited from their parents (familial ALS), however fully 90% develop the disease with no family history (sporadic ALS).  Patients with a family history have mutations in one of several genes that are associated with ALS development, while most patients develop the disease with no definable gene mutation.

Two of the genes that are mutated in a small percentage of familial ALS patients, make proteins that, in turn play important roles in regulating the production of other proteins needed to keep cells healthy.  These two proteins are called TDP-43 and FUS, and both influence the production of cell proteins by acting at the most elementary levels of gene expression – they act by altering DNA and RNA function.

While the genes responsible for making TDP-43 and FUS are actually mutated in only a very small number of ALS patients; when the brains and spinal cords of ALS patients who have died of the disease are examined – more than 90% of all ALS patients have altered patterns of these proteins in their motor neurons. So, in the majority of ALS patients, it is proposed that a combination of genetic susceptibility and environmental stress contribute to the altered patterns of TDP-43 and FUS in neurons.

The altered expression of these two proteins in ALS patients disrupts their ability to carry out their normal roles regulating DNA and RNA function in the cells, that eventually leads to the death of the motor neurons.

Progranulin, a protein found in all living animals, has a potent ability to protect neurons that are under stress from ALS. Importantly, in preclinical studies we and others have demonstrated that progranulin can correct the cellular defects caused by the altered patterns of TDP-43 and FUS proteins in motor neurons.  We are developing a specific form of progranulin called ALPHA-602 for the treatment of ALS patients.