Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined...
Patent
1988-12-15
1992-01-21
Weimar, Elizabeth C.
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
424570, 4351723, 4352402, 435948, 935 62, 935 70, 514 44, A61K 3500, A61K 4800, C12N 1500
Patent
active
050826700
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the use of recombinant technology for genetic modification of donor cells for grafting into the central nervous system (CNS) of a subject to treat defects, disease or damage of the CNS. More specifically, the invention relates to the insertion of a gene encoding a molecule having ameliorative effects on cells including neurons into donor cells such that when the donor cells are grafted into the CNS the molecule is expressed and exerts its effects on diseased or damaged cells.
BACKGROUND OF THE INVENTION
Attempts to repair the mammalian brain or replace CNS functions resulting from defects or following disease or damage to the CNS are hampered by an incomplete understanding of the complex structure-function relationships in the CNS. Although knowledge of some basic principles of cell function in the brain has advanced greatly in recent years, understanding of interactions between clusters of cells or systems and cell circuits in different regions of the brain and their relationship to the outward manifestations of behavior and neurological function lags far behind. Difficulties in approaching these problems have been caused, in part, by the large number of different cell types in the mammalian CNS and the number and complexity of their connections. In addition, the blood-brain barrier makes access to the brain for diagnosis, treatment and the design of new therapies more difficult.
In spite of the absence of sophisticated knowledge of pathophysiology of most normal or abnormal brain functions, some attempts at pharmacological therapy for CNS dysfunction have already become useful and effective. These include the use of psycho-active drugs for psychiatric disorders such as schizophrenia, and specific replacement therapy in the rare cases in which the biochemical and cellular bases of the CNS disorder are relatively better understood, as in Parkinson's disease. At the core of most therapeutic approaches is the objective of replacing or reactivating a specific chemical function in the brain that has been lost as a consequence of disease or damage.
Intracerebral neural grafting has emerged recently as an additional potential approach to CNS therapy. The replacement or addition of cells to the CNS which are able to produce and secrete therapeutically useful metabolites may offer the advantage of averting repeated drug administration while also avoiding the drug delivery complications posed by the blood-brain barrier. (Rosenstein, Science 235:772-774 (1987)). While the concepts and basic procedures of intracerebral grafting have been known for decades, most of the factors that optimize the survival of grafted cells have only recently come to be investigated and partially understood. (Bjorklund et al., in Neural Graftinc in the Mammalian CNS, p. 709, Elsevier, Amsterdam (1985); Sladek et al., in Neural Transplants: Development and Function, Plenum Press, N.Y. (1984)). Several factors critical for reliable and effective graft survival have been identified, including the following:
(1) Age of the donor: efficiency of grafting is reduced with increasing age of donor cells.
(2) Age of the host: young recipients accept grafts more readily than older ones.
(3) Availability of neuronotrophic factors in the host and donor tissue: wound-induced neurotrophic factors enhance graft survival.
(4) Immunological response: the brain is not totally an immunologically privileged site.
(5) The importance of target-donor matching: neurons survive better when they are grafted to a site which they would normally innervate.
(6) Vascularization: it is critical that the grafts be vascularized rapidly or otherwise sufficiently well nourished from the environment.
As these critical factors have become recognized and optimized, intracerebral grafting has become a valid and reliable tool for neurobiologists in the study of CNS function and potentially for clinicians for the design of therapies of CNS disease. This approach has reached a level of experimental clinical applic
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Friedmann Theodore
Gage Fred H.
Rosenberg Michael B.
Chambers Jasemine C.
The Regents of the University of California
Weimar Elizabeth C.
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