From the Medical Science Bulletin
Trophic factors: protecting against PD and ALS
One of the most promising areas in neuropharmacologic research is the study
of trophic factors, naturally occurring peptides (small proteins) that
protect and support the neuron. These so-called nerve growth factors are
under investigation for treating AD, PD, and ALS, and also for the
treatment of trauma and ischemic injury.
A series of papers recently published in the journal Nature (January 26,
1995) describe the neuroprotective efficacy of glial-cell-line- derived
neurotrophic factor (GDNF). This peptide appears to enhance the survival of
both dopaminergic neurons in the midbrain and motor neurons in the spinal
cord, suggesting that it may be useful for the treatment of PD and ALS.
PD is a progressive and ultimately fatal neurodegenerative disease
afflicting about 1.5 million Americans. Symptoms-- tremor, akinesia,
rigidity--occur when there is a profound deficiency of the neurotransmitter
dopamine, resulting from the degeneration of dopaminergic neurons that
project to
the striatum. ALS is another progressive and fatal neurodegenerative
disorder. It is less common than PD, afflicting about 20,000 people in the
United States, but it generally has a poorer prognosis. Survival ranges from
a few months to decades, with a median of 37 to 49 months.
Symptoms--weakness, wasting, and fasciculation and fibrillation of muscle
fibers--are the result of the loss of motor neurons in the cerebral cortex,
the motor nuclei of the cranial nerves, and the anterior horn cells in the
spinal cord. Symptoms can begin in the arms, legs, or oropharynx (dysarthria
and dysphagia). Known prognostic factors include age at onset, site of
onset, duration of
weakness, and degree of clinical disability and respiratory function. Some
investigators believe that the disease results when glutamate, the primary
excitatory neurotransmitter in the central nervous system, accumulates to
toxic levels at synapses and causes the death of neurons via a
calcium-dependent pathway. (Bensimon G et al. N Engl J Med. 1994; 330:
585-591. Lipton SA, Rosenberg PA. N Engl J Med. 1994; 330: 613-626. Rowland
LP. N Engl J Med. 1994;330:
636- 637.)
Two of the papers in Nature describe the efficacy of GDNF for protecting
dopaminergic neurons, and another two describe its efficacy for protecting
spinal motor neurons in addition to dopamine neurons.
Researchers at Synergen used GDNF to protect against damage by MPTP, a
neurotoxin that destroys dopaminergic tracts and causes severe Parkinsonism
in humans. GDNF was shown to
actually restore activity to cells already damaged by MPTP. Researchers at
Genentech used GDNF to enhance the survival of dopamine neurons cut at the
axon. Normally 50% of cut neurons degenerate, but after GDNF administration,
degeneration occurred in only 15% of the neurons. Oppenheim et al. found
that GDNF enhanced the survival of both midbrain dopamine neurons and spinal
motor neurons, while Yan et al. reported that GDNF is the most potent motor
neuron trophic factor found so far.
GDNF was first isolated from glial cells by Frank Collins, a biologist
working at Synergen (Boulder, CO). He published his findings in 1993 when
Synergen received a patent for GDNF; then Collins moved to Amgen (Thousand
Oaks, CA). Recently Synergen itself was acquired by Amgen. Apparently one
motivating factor in Amgen's decision to purchase Synergen was to obtain the
rights to GDNF. Collins is currently developing the peptide for use in the
treatment of PD.
GDNF may be a promising therapeutic candidate for PD and ALS, but laboratory
activity does not necessarily mean clinical efficacy. A similar nerve growth
factor developed by Regeneron Pharmaceuticals in Tarrytown, NY--ciliary
neurotrophic factor (CNTF)--failed to improve symptoms in ALS patients, and
administration was associated with hyperalgesia and weight loss. However,
Regeneron (now headed by Roy Vagelos, who recently retired as Merck's CEO)
continues to research neurotrophic factors. Amgen, Genentech, and several
other biotech companies are also studying nerve-growth factors, including
brain-derived neurotrophic factor and insulin-like growth factor-1. (Lindsay
RM. Nature. 1995;273:289-290. Tomac A et al. Nature. 1995; 273: 335-339.
Beck KD et al. Nature. 1995; 273: 339-341. Yan Q et al. Nature. 1995; 273:
341-344. Oppenheim W. Nature. 1995; 273: 344-346. Pfeiffer N. Gen Eng News.
1994;14[21]:1, 29.;Callison K et al. Transgenica. 1994; 1: 45-48)
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