A potential therapy for ALS June 2, 2013

Content Brief introduction about ALS and the field Proposal First an overview of how each component affects disease pathogenesis followed by my therapy idea

What is ALS? First described in 1869 by Dr. Jean Martin Charcot Neurodegenerative disorder, causes death of upper and lower motor neurons Average survival from symptom onset is 3 years Symptoms include progressive muscle weakness, atrophy and spasticity Also known as Lou Gehrig’s disease

ALS in numbers 285,200 people with ALS 16 deaths per day 180 failed trials 60 ongoing trials 1 approved drug ALS in numbers

Some things that have been done on the field Identification of several genes that cause FALS and some that also affect SALS Adoption of SOD1 transgenic mice as the standard model Several experiments involving neurotropic factors, antioxidants and protein-related compounds

ALS as a strategic move FDA orphan drug status Many things in common with other neurodegenerative diseases

Proposal (beta version)

RNA and ALS Many different defects in RNA editing have been found in ALS The individual functional changes are just known for a few sites. Most common RNA editing defects are in SOD1, TDP-43 and FUS. On pipeline targets are SOD1 and miR-206

siRNA, NGS and a personalized therapy Use NGS to search for patient-specific candidate RNA editing events. Use engineered nanoparticles to deliver and self-assemble double-stranded small interfered RNA (siRNA) siRNA can be used for sequence-specific gene silencing. Proposal

Additional Components These are marked as additional because I think they are important components for an effective ALS therapy but there is already people working on what I am suggesting. Out of these additional components, the ones I think are most promising (and which happen to be the less studied: 1 company working on each) are glial transplantation and microtubule stabilization.

Glia and ALS Glial cells have been associated with neurotoxicity and the inflammatory response associated with neurodegeneration In ALS, both microglia and astrocytes become activated and toxic and there is a significant loss of gray matter oligodendrocytes; this is an important non-cell autonomous mechanism. There is only 1 company working on glial transplantation

Glia transplantation Implant neural precursor cells (NPCs) and glial restricted precursors (GRPs) into the CNS of patients with ALS Glial cells can be derived from NPCs and by GRPs. Re-myelination can also be achieved through transplantation of glial cells. This is also a factor relevant to ALS (secondary). This has already been done (2008) and significantly increased lifespan in SOD1 mice Proposal

Microtubules and axonal transport Microtubule transport is essential for survival of motoneurons and the stability of microtubules is presumed to be essential to maintain the axonal transport of synaptic vesicles and proteins. Autophagic failure might also be related to altered microtubule dynamics

Microtubule Stabilization Modulate microtubule polymer (MT) dynamics by inducing microtubule modulating agents. that can restore axonal transport and protect neurons in vitro. that prolonged life by 26% in SOD1 mice Bristol-Myers Squibb is working on this Proposal

Protein aggregates in ALS Protein aggregates are seen in all cases of ALS, although there are many different kinds of aggregates. These aggregates are thought to be a main pathogenic mechanism and are related to inflammation and glia activation The most commonly seen aggregates are burina bodies (present in 80-100% of SALS cases), and other types of aggregates include ubiquitin immunoreactive inclusions; and neurofilament, tau and peripherin aggregates.

Oxidative stress Oxidative stress in ALS is caused by many factors, mainly increased production of nitric oxide and peroxynitrite by damaged neurons. This also activated astrocytes Levels of ROS are twice that of normal in spinal cords of patients with ALS mRNA oxidation is also common and happens before motor neuron degeneration and symptom onset

Specific proposal (summary) Use NGS to search for patient-specific candidate RNA editing events. Use engineered nanoparticles to deliver and self-assemble siRNA Implant neural precursor cells (NPCs) and glial restricted precursors (GRPs) into the CNS of patients with ALS Modulate microtubule polymer (MT) dynamics by inducing microtubule modulating agents