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Neuroprotective Drugs for Spinal Cord Injury

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: PHS2001-2
Agency Tracking Number: 1R41NS040586-01A1
Amount: $208,726.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: N/A
Solicitation Number: N/A
Solicitation Year: N/A
Award Year: 2001
Award Start Date (Proposal Award Date): N/A
Award End Date (Contract End Date): N/A
Small Business Information
160 2ND ST CAMBRIDGE, MA 02142
United States
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (202) 687-1196
Business Contact
Phone: (617) 492-5554
Research Institution

DESCRIPTION: (Adapted from the Applicant's Abstract) Traumatic spinal cord
injury (SCI) leads to permanent loss of motor function and control of function
below the level of the injury. A significant portion of the loss is due to
secondary factors rather than the initial trauma. These factors include
increased extracellular concentrations of glutamate which have demonstrated
excitotoxicity. Ionotropic glutamate antagonists, administered acutely after
injury showed promise as neuroprotective agents which has not been borne out by
clinical trials due to adverse side effects. Recently developed metabotropic
glutamate receptor agonists also show neuroprotective characteristics in tissue
culture studies and are expected to have a more favorable side effect profile.
Preliminary studies of a clinically relevant model of SCI in rodents have
adapted it for relatively rapid assay of neuroprotective effects. The present
proposal will test 3 of the most promising metabotropic glutamate receptor
agonists in this assay and compare them to a known ionotropic glutamate
receptor antagonist for neuroprotective effects. Dose response curves at a
single time point will be constructed. Then the most efficacious dose of each
compound will be tested for therapeutic window after injury.

On average, 11,000 traumatic spinal cord injuries (SCI) are reported every year in
the United States. Currently, there are no effective medications for the treatment
of SCI. The development of effective pharmacotherapies that reduce the severity
of injury following a traumatic event could as much as $400 billion on future direct
and indirect SCI lifetime costs in the United States alone. The medications developed
in this program would also be expected to be efficacious for the treatment of traumatic
head injury, stroke and related disorders.

STRENGTHS: This is a resubmitted Phase I proposal. The current application has
retained the strengths of the original proposal and corrected the deficiencies
noted in the first review. The preliminary studies demonstrate that the 3 drugs
to be investigated have shown neuroprotective effects in several different
neuronal culture excitotoxicity studies. The present proposal will produce dose
response curves for all 3 drugs in comparison with vehicle and with a known
neuroprotective ionotropic antagonist. The time of administration will be held
at 5 minutes post-injury for all the studies. The use of the ionotropic
antagonist for comparison is relevant and useful. A second set of experiments
will use the most efficacious dose of each drug and vary the time of delivery
post-injury to determine the therapeutic window for administration. The second
set of studies do not use strict controls (i.e. administration of vehicle at
each time point) but rather use a single group of untreated SCI rats as
control. The investigator has justified this control approach by citing
previous studies in the laboratory which show no effect of vehicle
administration at differing time points. Assessment of neuroprotective capacity
will be by determination of numbers of surviving ventral horn motor neurons at
lesion site and at discrete distances fore and aft of the site of contusion.
Animals will be sacrificed at 24 hours, a time point which has been determined
to reflect accurately the level of damage 1 month after injury. Since loss of
glia cells has also been associated with loss of function, the investigator
will assess numbers of glia, both astrocytes and oligodendrocytes, if time

The proposal is well thought out, well written and logical in its flow of
experiments. The investigator is well qualified to perform the work. The data
from these studies could form the foundation for additional preclinical studies
of loss of function in the rodent SCI model and later, human clinical studies.
The background and preliminary studies sections suggest that metabotropic
glutamate receptor agonists may hold the key to neuroprotection for traumatic
injury, inadvertent surgical injury and perhaps neurodegenerative disorders.

WEAKNESSES: There are few weaknesses in this application. The investigator
states that the T8 incomplete SCI model induces a respiratory deficit, but this
deficit is never explained, nor does it appear to be a measure that will be
used to assess loss of function. Clearly, since the accidental mortality in
this model is less than 10 percent, the deficit is not lethal. Is it possible
to quantify and use this as an assessment of loss of function? Another minor
point is that the volume of solution being injected to the injury site is not
defined. It is presumed that a single volume will be used and the concentration
of drug varied, but this is not spelled out.

* Information listed above is at the time of submission. *

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