Download - A potential therapy for ALS
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A potential therapy for ALS
June 2, 2013
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Content
• Brief introduction about ALS and the field • Proposal – First an overview of how each component affects
disease pathogenesis followed by my therapy idea
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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
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ALS in numbers
285,200 people with ALS
16 deaths per day
180 failed trials
60 ongoing trials
1 approved drug
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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
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ALS as a strategic move
• FDA orphan drug status• Many things in common with other
neurodegenerative diseases
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Proposal(beta version)
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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
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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
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Additional ComponentsThese 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.
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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
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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
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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
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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
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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.
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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
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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