A potential therapy for ALS

1. A potential therapy for ALS June 2, 2013

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

3. 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

4. ALS in numbers 285,200 people with ALS 16deathsper day 180 failed trials 60 ongoing trials 1 approved drug

5. 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

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

7. Proposal(beta version)

8. 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

9. 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) • siRNAcan be used for sequence-specific gene silencing. Proposal

10. 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.

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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