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 16 deaths per day
180 failed trials
60 ongoing trials
1 approved drug
ALS in numbers

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)
siRNA can 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 % 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