2005 Research
Highlights
THERAPEUTICS
Drug Discovery
- Clinical trials of the drug ceftriaxone, the most promising
from the earlier NIH-sponsored screening, are in the last planning
stages that precede clinical trials recruiting. The move follows
work by Jeffrey Rothstein’s team showing that the drug significantly
extends life in ALS mouse models. The drug talampenel, which blocks
specific glutamate receptors, is in the therapy pipeline, approaching
a Phase II trial next year.
- Results of clinical trials of Celebrex have crossed the drug
off the therapy list
Stem Cell Therapy
- Douglas Kerr hit what he calls “stem cell nirvana”
this year, showing that embryonic stem cell-derived motor neurons
can reach skeletal muscle targets in animal models, that they
form active neuromuscular junctions and result in the animals’
partial recovery from paralysis.
- Ahmet Höke has shown certain neural stem cells produce
higher amounts of growth factors and other cell promoters than
others, a consideration for future therapy.
Neuroprotection
- A team led by Packard advisor Peter Carmeliet and Packard scientist
Wim Robberecht infused the cerebrospinal fluid of rat ALS models
with the agent VEGF. The rats’ normally quick onset of disease
parallels bulbar ALS. VEGF’s protective effect on motor
neurons significantly extended life.
Gene-based Approaches
- In blocking the most common familial ALS gene with a direct
nervous system infusion of antisense oligonucleotides—a
technique that damps unwanted gene expression—Don Cleveland
reports slowing disease in ALS rat models. Clinical trials are
likely, he says, in 2006.
- Jeffrey Johnson introduced
a gene that turns on a master neuroprotective switch into muscles
of ALS model mice. It significantly slows motor neuron damage
and delays paralysis.
Nerve Repair
- Ahmet Höke discovered that the hormone-like agent pleiotrophin
sustains neurons in model cultures of spinal cord injury and encourages
their regrowth.
BASIC RESEARCH
Center scientists still push to understand the underlying basis
of ALS. This year, Don Cleveland’s animal model studies
showed that microglia, the nervous system’s resident immune
cells, play a key part in the progression of the disease. In
studying a microglia-squelched mouse model he’s just created,
Jean-Pierre Julien hopes to clarify their role. Further work
by Richard Ransohoff has
discovered that microglia have a potential Achilles’ heel,
a possible therapeutic target.
In motor neuron studies, Jonathan Glass found that ALS appears
in neurons far earlier than anyone had suspected. Also appearing
far earlier, says Elizabeth Fisher, are defects in the cells’
internal transport system. The flaws apparently advance motor neuron
death, and overcoming them, she’s found, extends animal models’
lives.
In work on the biology of neuron growth and repair, Marie Filbin
has mapped out key steps in a naturally occurring inhibition of
nerve regrowth that occurs in the spinal cord following injury—work
that offers possible drug targets.
Models
Philip Wong and
Center colleagues successfully engineered a mouse model to reveal
more about the mechanism of the recently discovered ALS4 gene
in this inherited form of the disease. Wong also developed a new
model mouse that more closely resembles the most common ALS and
that highlights a potentially crucial problem in neurons.
FYI
In 2004–2005, our scientists have published more than 92
ALS-related papers in respected journals, including Science, Nature,
The Journal of Neuroscience, New England Journal of Medicine, The
Journal of Cell Biology and Neuron.
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