TARGETS OF THERAPEUTIC STRATEGIES

Disrupted Pathways Leading to ALS

The first identified ALS gene, SOD1, had been identified because of unfortunate families that carry mutations in SOD1 which leads to the development of ALS. The completion of the human genome project, which mapped the code of the human DNA, has given scientists an incredible tool to identify mutations that can lead to disease. Physicians have asked tens of thousands of ALS patients to participate in DNA sequencing studies to identify genes that can lead to the development of ALS. Through these efforts combined with the study of ALS families, the scientific community has now been able to identify almost 30 different genes that can cause ALS. Interestingly, a number of these genes have pointed to key cellular processes which appear to be causal to the disease when disrupted such as RNA binding and transport, immune system abnormalities and cellular waste clearance pathways, also called autophagy and mitophagy pathways.

RNA molecules contain the information in cells for the production of proteins. Because motor neurons, which are the cells that degenerate in ALS patients in the spinal cord, have very long extensions that can reach all the way to the muscles in hands and feet, the RNA must be transported over long distances to make proteins everywhere in the cell. It is therefore likely that a problem with the transport of RNA will have a severe impact in motor neurons specifically. Mutations in several ALS genes, such as FUS, TDP43 and C9orf72 are known to impact the regulation of RNA inside the cells.

Because as people get older, toxic proteins are generated more frequently, it is important that they are cleared rapidly from cells to keep them functioning properly. There are two processes that are important for this. The immune system which helps to clean the environment of cells in the body and the waste clearance pathways inside of cells that can clear the buildup of toxic proteins and through which old broken cellular components responsible for energy production are recycled. Mutations in several ALS genes, such as TBK1, Optineurin, P62 and Ubiquilin-2 can have an impact on both of these processes.
Recently discoveries point out that mutations in different ALS associated genes work together in development of the disease. Through this knowledge scientist can puzzle together which pathways to target in certain patients and how to restore their function and stop the development of the disease.
Through continued sequencing it is expected that more genes will be identified that will give us an even better understanding of ALS and of the opportunities to develop precision medicine therapies for certain groups of ALS patients.

Targets of Therapeutic Strategies

Cirulli, E.T., et al., Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science, 2015. 347(6229): p. 1436-41.

Toxic Proteins

Mutations in the genes that code for proteins can sometimes cause the proteins to become toxic. This is the case for C9orf72 and for SOD1, FUS and TDP43. We can then try to make therapies that target the toxicity of these proteins. QurAlis is doing this exactly for toxic proteins that are made by C9orf72 mutations. Cells make toxic C9orf72 proteins after which they spread throughout the brain and spinal cord through the brain and spinal liquids. QurAlis has developed a method to destroy these toxic proteins in the brain fluids which we are now making into our CSF device. We are also developing a medicine that will stimulate the removal of toxic proteins from within the cells by stimulating the waste clearance pathway regulated by the TBK1 protein.

Toxic Proteins

Gomez-Deza, J., et al., Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun, 2015. 3: p. 38.

Excitotoxicity

20-50% of ALS patients show hyperexcitability in their motor system. This means that the neurons that control muscles fire too much. This overactivity of the motor system leads to a fast progression of the disease in ALS patients. One of the reasons for this is that when cells fire too much there is an increase of calcium that flows into the cells which at certain high levels is a signal for cells to initiate a cell termination program. But even if this high level is not immediately reached, the cells get stressed and produce larger amounts of free radicals and toxic proteins. The removal of these toxic molecules is also slowed down which leads to impaired function and ultimately to withdraw of nerves from the muscles leading to paralysis. A key molecular mechanism that regulates the excitability of the motor system is the potassium channel Kv7.2/7.3. By studying motor neurons generated from stem cells from ALS patients we have discovered that this potassium channel is downregulated in the motor system leading to hyperexcitability and exitotoxicity. Others have shown that a receptor that recognizes signaling molecules that tell the cell to fire, the AMPA receptor, is upregulated in spinal motor neurons leading to overactivation. Together these two mechanisms are detrimental for ALS patients and therefore targets of therapeutic strategies.

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