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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
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, TDP43 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