Surgery – Miscellaneous – Methods
Utility Patent
1998-06-30
2001-01-02
Isabella, David J. (Department: 3738)
Surgery
Miscellaneous
Methods
C424S570000
Utility Patent
active
06167888
ABSTRACT:
BACKGROUND FOR THE INVENTION
1. Field of the Invention
The invention relates to methods for treating spinal cord injuries in a mammal. Specifically, the invention relates to a method for inducing partial recovery of voluntary motor function in a mammal after disruption of corticospinal projections in the spinal cord.
2. History of the Art
The mammalian spinal cord shows little spontaneous recovery after injury. Furthermore, although regeneration of damaged spinal cord tissues (e.g., axons and neurons) can sometimes be induced through treatment, the treated animals still do not usually recover whatever voluntary motor function was lost to the injury.
The degree of motor function loss varies with the identity of the damaged tissue and the extent of damage incurred, as well as with species. For example, the rubrospinal tract influences movement through direct and reciprocal spinal motor projections that reflect activity of the rubro-cortico-cerebellar premotor pathway. The vestibulospinal and reticulospinal tracts affect postural control and balance during locomotion. Specialization in the vestibular system in particular has been important for the evolution of bipedal locomotion in humans. However, impairments in voluntary motor function after spinal cord injury in humans are most often attributed to disruption of corticospinal tract (CST) projections.
In rats, a species frequently used to study spinal cord regeneration, CST lesions have been reported to impair skilled motor movements, such as reaching, preferred limb use, and “placing” responses (reflex limb withdrawal to touch). Studies in cats and non-human primates report that the CST is involved in voluntary modification of gait, inducing alterations in amplitude, duration and temporal patterns of muscle activity during locomotion through both direct projections to motor neurons and through modification of activity of spinal cord pattern generators. In humans, some voluntary motor function can occasionally be recovered spontaneously despite isolated lesions of the CST, although function is generally inferior to the prelesioned state.
Two reports of partial functional recovery resulting from regrowth of host projections after spinal cord injury have recently been published. In one approach, CNS myelin-associated growth inhibitors were neutralized (Bregman B S, Kunkel-Bagden E, Schnell L, Dai H N, Gao D, Schwab M E (1995) Recovery from spinal cord injury by antibodies to neurite growth inhibitors. Nature 378:498-501), resulting in regrowth of axons through host white matter. In a second study, delivery of acidic fibroblast growth factor reportedly generated growth responses from all supraspinal systems studied, resulting in some functional recovery after complete spinal cord transections (Cheng H, Yihai C, Olson L. (1996) Spinal cord repair in adult paraplegic rats: Partial restoration of hind limb function. Science 273:510-513). Regenerating axons in the latter experiment were specifically directed toward host gray matter to avoid myelin-based inhibitors. These findings highlight the importance of defining appropriate growth terrains for injured adult CNS axons and of identifying specific growth-promoting neurotrophic factors.
SUMMARY OF THE INVENTION
The invention provides a method for treating a mammal which has suffered an injury to its spinal cord involving the CST and has lost some voluntary sensorimotor function as a consequence of the injury. Uninjured spinal cord tissue is not affected by the inventive treatment method. According to the method, a CST neurotrophin (such as NT-3) is delivered to the mammal to act on the spinal cord at the site of the CST lesion. Practice of the method of the invention not only produces regrowth of CST projections in the presence of gray matter tissue, but also surprisingly results in the restoration of a degree of the lost voluntary motor function.
Specifically, consistent with expectations, animals treated according to the invention undergo some growth of CST axonal projections at the site of a spinal cord injury. However, in stark contrast to prior experience with many treatments for spinal cord injuries, the treated animals also recovered some motor function whose loss was attributable to the CST injuries inflicted on each animal prior to treatment. Interestingly, voluntary motor function is restorable through use of the method of the invention to treat CST lesions in animals whose spinal cord injuries extend beyond the CST.
Exposure of the lesions to CST neurotrophin can be prolonged for a time sufficient to induce functional recovery (as compared to, for example, single dosing with NT-3) by grafting syngenic cells which have been engineered to express CST neurotrophin to the site of the CST lesions in the presence of an appropriate growth substrate (i.e., host gray matter). Another method for delivery of the CST neurotrophin to CST lesions supplies an CST neurotrophin coding recombinant expression vector into the lesioned spinal cord.
Treatment of CST lesions according to the invention may be supplemented by any treatment or therapy appropriate to the nature and degree of injury in the affected mammal.
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Gage Fred H.
Grill Rav
Tuszynski Mark H.
Foley & Lardner
Isabella David J.
O'Hara Kelly
The Regents of the University of California
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