Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1999-12-10
2001-07-24
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093210, C424S093100, C424S093200, C514S04400A
Reexamination Certificate
active
06264943
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
The present application is a continuation-in-part of U.S. application Ser. No. 07/599,802, filed Oct. 19, 1990, the entire contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention in the field of neuroscience and medicine relates to methods for implantation or transplantation of cells into the mammalian brain, useful in treating neurological disorders.
2. Description of the Background Art
The clinical management of numerous neurological disorders has been frustrated by the progressive nature of degenerative, traumatic or destructive neurological diseases and the limited efficacy and the serious side-effects of available pharmacological agents. Because many such diseases involve destruction of specific “neuronal clusters” or brain regions, it has been hoped that grafting of neural cells or neuron-like cells directly into the affected brain region might provide therapeutic benefit. Cell transplant approaches have taken on a major emphasis in current Parkinson's disease research, and may prove useful in promoting recovery from other debilitating diseases of the nervous system including Huntington's disease, Alzheimer's disease, severe seizure disorders including epilepsy, familial dysautonomia, as well as injury or trauma to the nervous system. In addition, the characterization of factors which influence neurotransmitter phenotypic expression in cells placed into the brain may lead to a better understanding of normal processes and indicate means by which birth defects resulting from aberrant phenotypic expression can be therapeutically prevented or corrected. Neurons or neuronal-like cells can be grafted into the central nervous system (CNS), in particular, into the brain, either as solid tissue blocks or as dispersed cells. However, to date, a number of problems of both a technical and ethical nature have plagued the development of clinically feasible grafting procedures.
Parkinson's disease results from a selective loss of dopaminergic nigrostriatal neurons, resulting in a loss of input from the substantia nigra to the striatum. Solid grafts of tissues potentially capable of producing dopamine, such as adult adrenal medulla and embryonic substantia nigra (SN), have been used extensively for experimental grafting in rats and primates treated with 6-hydroxydopamine (6-OHDA) to destroy dopaminergic cells (Dunnett, S. B. et al.,
Brain Res.
215: 147-161 (1981); ibid. 229:457-470 (1981); Morisha, J. M. et al.,
Exp. Neurol.
84:643-654 (1984); Perlow, M. J. et al.,
Science
204:643-647 (1979)). Grafts of embryonic SN have also been used as therapy for primates lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), which produces a Parkinson's-like disease (Redmond, D. E. et al.,
Lancet
8490:1125-27 (1986)).
Stenevi et al. (
Brain Res.
114:1-20 (1976) found that the best results were obtained with fetal CNS neurons which were placed next to a rich vascular supply. In fact, a review of the literature reveals that tissue from almost every area of the fetal brain can be successfully transplanted if care is taken with procedural details (see, for example, Olson, L. A. et al., In:
Neural Transplants: Development and Function
, Sladek, J. R. et al., eds, Plenum Press, New York, 1984, pp. 125-165).
Embryonic tissue provides an excellent source of cells which will differentiate in a foreign environment and become integrated with the host tissue. For example, grafts of embryonic SN into 6-OHDA treated rats have been shown to produce dopamine, to reduce apomorphine- or amphetamine-induced rotation, to alleviate sensory deficits and to make synapses in the host striatum (Dunnett et al., Morisha et al., Perlow et al., supra). Grafted neurons are also spontaneously active, thus mimicking normal adult SN neurons (Wuerthele, S. M. et al., In
Catecholamines, Part B
, (E. Usdin et al., eds.), A. R. Liss, Inc., New York, pp. 333-341).
In contrast to successful grafting of fetal neural tissue, mature CNS neurons have never been found to survive in transplants (Stenevi, U. et al.,
Brain Res.
114:1-20 (1976)).
The reason fetal CNS neurons survive grafting procedures while adult neurons do not, while uncertain, is probably related to several factors. First, fetal neurons are less affected by low oxygen levels than mature neurons (Jilek, L., In:
Developmental Neurobiology
, Himwich, W. A., ed., C. C. Thomas Publisher, Springfield, Ill., 1970, pp. 331-369), and grafting procedures necessarily involve periods of anoxia until an adequate blood supply to the transplant is established. Secondly, fetal neurons seem to survive best when they are taken during a rapid growth phase and before connections are established with target tissues (Boer, G. J. et al.,
Neuroscience
15:1087-1109, (1985)). Also, fetal tissue may be especially responsive to growth (or “survival”) factors which are known to be present in the milieu of the damaged host brain (Nieto-Sampedro, M. et al.,
Science
217:860-861 (1982);
Proc. Natl. Acad. Sci. USA
81:6250-6254 (1984)).
However, despite the promise of fetal tissue and cell transplants, the art has turned to alternate sources of donor tissues for transplantation because of the ethical, moral, and legal problems attendant to utilizing fetal tissue in human medicine. These sources include neural and paraneural cells from organ donors and cultured cell lines. (See, for example: Gash, D. M. et al., In:
Neural Grafting in the Mammalian CNS
, Bjorklund, A. et al., eds, Elsevier, Amsterdam, 1985, pp. 595-603; Gash, D. M. et al.,
Science
233:1420-22 (1986)).
Although early clinical experiments using the grafting approach did not result in long-lasting effects, an initial report of one study appeared more promising (Madrazo et al., Soc.
Neurosci. Abstr.
12:563 (1986); for an overview, see: Lieberman, A. et al.,
Adv. Tech. Stand. Neurosurg.
17:65-76 (1990), which is hereby incorporated by reference). However, the surgical procedure used required craniotomy or full “open brain” surgery in which a portion of healthy striatum was removed and replaced with “chunks” of fetal adrenal gland. The therapeutic results obtained were somewhat controversial. However, both the need for serious neurosurgery in an already debilitated population and the need to use fetal tissue makes this approach undesirable.
In further human studies (Lieberman, supra; Lindvall, O.,
J. Neurol. Neurosurg. Psychiat.,
1989, Special Supplement, pp. 39-54; Bakay, R. A. E.,
Neurosurg. Clin. N. Amer.
1:881-895 (1990)), autologous grafts have been attempted to replace the need for fetal material. In this procedure the patients first underwent initial abdominal surgery for the removal of a healthy adrenal gland. The patient then was subjected to similar neurosurgery as that for the fetal adrenal transplant. The surgical morbidity-mortality for the combined adrenalectomy
eurosurgery was expectedly high. The ultimate therapeutic result was claimed to be as high as 30% but may have been as low as one patient in the series of six. There was no evidence that the adrenal material transplanted into these patients survived.
Several additional observations suggest that grafting adrenal cells should be a viable approach. Adrenal medullary cells are derived from the neural crest and, like sympathetic neurons, grow processes in vivo or in vitro in response to nerve growth factor (NGF) (Unsicker, K. et al.,
Proc. Natl. Acad. Sci. USA
75:3498-3502 (1978)). Solid grafts of adrenal medulla from young rats can survive in the brain of 6-OHDA treated rats for at least 5 months, produce dopamine and reduce apomorphine induced rotation (Dunnett et al., supra; Freed, W. J. et al.,
Ann. Neurol.
8:510-519 (1980); Freed, W. J. et al.
Science
222:937-939 (1983)). These observations suggest that given the appropriate environment, adrenal medullary cells have the potential for growing catecholamine-synthesizing fibers into brain tissue.
The potential for neuronal differentiation
Clark Deborah J. R.
Morrison & Foerster / LLP
New York University
Sorbello Eleanor
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