Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of detaching cells – digesting tissue or establishing...
Reexamination Certificate
1995-04-19
2001-09-25
Saoud, Christine J. (Department: 1647)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of detaching cells, digesting tissue or establishing...
C435S325000
Reexamination Certificate
active
06294383
ABSTRACT:
BACKGROUND OF THE INVENTION
With the exception of
L
-DOPA pharmacological administration for Parkinson's disease, neurodegenerative diseases in general lack effective treatment. Previous studies of neurodegenerative diseases suggest that symptoms arise secondary to defects in local neural circuitry and cannot be treated effectively with systemic drug delivery. Consequently, alternative treatments for neurodegenerative diseases have emerged. Such treatments include transplantation of genetically engineered cells (See e.g., Breakefield, X.O. et al. (1989)
Neurobiol. Aging
10:647-648; Gage, F. H. et al. (1987)
Neuroscience
23:795-807; Horellou P. et al. (1990)
Eur. J. Neurosci.
2:116-119; Rosenberg, M. B. et al. (1988)
Science
242:1575-1578; Wolff, J. A. et al. (1989)
Proc. Natl. Acad. Sci. USA
86:9011-9014) or fetal cells (See e.g., Björklund, A. et al. (1983)
Acta. Physiol. Scand.
Suppl. 522:1-75; Dunnett, S. B. et al. (1990) in Brain Repair (eds. Björklund, A. et al.) Wenner-Gren International Symposium Series 56:335-373 (McMillan Press, London); Isacson, O. et al. (1984)
Nature
311;458-460) into the area of neurodegeneration in an effort to reconstitute damaged neural circuits, and to replace lost neurons and neurotransmitter systems.
Engineered cells can be derived from cell lines or grown from recipient host fibroblasts or other cells and then modified to produce and secrete substances following transplantation into a specific site in the brain. Neuroactive substances amenable to this delivery mode include neuropeptides and chemical transmitters. For example, one group of researchers developed a biological system in which genetically engineered nerve growth factor-producing rat fibroblasts, when implanted into the rat striatum prior to infusion of neurotoxins were reported to protect neurons from excitotoxin-induced lesions (Schumacher, J. M. et al. (1991)
Neuroscience
45(3):561-570). Another group which transplanted rat fibroblasts genetically modified to produce
L
-DOPA or dopamine into 6-hydroxydopamine lesions of the nigrostriatal pathway in rats reported that the transplanted fibroblasts reduced behavioral abnormalities in the lesioned rats (Wolff, J. A. et al. (1989)
Proc. Natl. Acad. Sci. USA
86:9011-9014). Alternative to genetically engineered cells, cells to be implanted into the brain can be selected because of their intrinsic release of critical compounds, e.g., catecholamines by PC12 cells and nerve growth factor by immortalized hippocampal neurons.
Transplantation of cells engineered to produce and secrete neuroactive substances can be used alone or in combination with transplantation of fetal neural progenitor cells into areas of neurodegeneration in the brain. In order to repair functional connections damaged by neurodegeneration in, for example, the striatum, cells transplanted into the area of striatal neuron loss must re-establish synaptic connectivity with neurons in a number of target structures located a considerable distance from the area of neurodegeneration. Axonal tracing of connections of intrastriatal allografts in rats demonstrate that both afferent and efferent connections are established between graft neurons and host neurons in appropriate areas (Labandeira-Garcia, J. L. et al. (1991)
Neuroscience
42:407-426; Liu, F. C. et al. (1990)
J. Comp. Neurol.
295:1-14; Wictorin, K. et al. (1988)
Neuroscience
27:547-562; Wictorin, K. et al. (1989)
Neuroscience
30:297-311; Xu, Z. C. et al. (1991)
J. Comp. Neurol.
303:22-34) and host-graft connections have been substantiated by electrophysiological and ultrastructural analysis. Rutherford, A. et al. (1987)
Neuroscience Lett.
83:275-281; Xu, Z. C. et al. (1991)
J. Comp. Neurol.
303:22-34. However, the extent of efferent connections from striatal allografts is limited, with respect to number of connections (Walker, P. D. et al. (1987)
Brain Res.
425:34-44; Wictorin, K. et al. (1989)
Neuroscience
30:297-311) and with respect to connections to distant targets (McAllister, J. et al. (1989)
Brain Res.
476:345-350; Pritzel et al. (1986); Wictorin, K. et al. (1989)
Neuroscience
30:297-311; Zhou, H. F. et al. (1989)
Brain Res.
504:15-30). There is a need, therefore, for sources of neural progenitor cells and methods of neural transplantation which promote or enhance development of efferent connections from the transplant to the recipient brain tissue and connections with distant recipient brain targets.
In order to replace dopaminergic cells damaged by neurodegeneration in, for example, the substantia nigra, cells transplanted into the area of dopaminergic neuron loss must saturate the striatum with terminals and produce dopamine via a feedback control system. Cells which are engineered to express enzymes which act in the biosynthesis of dopamine are known to constitutively secrete dopamine. Kang, U. J. et al. (1993)
J. Neurosci.
13(12):5203-5211. The constitutive secretion of dopamine was reported to be without significant storage capacity in vesicles or regulation at the level of secretion. Kang, U. J. et al. (1993)
J. Neurosci.
13(12):5203-5211; See also Fisher, L. J. et al. (1993)
Ann. N.Y Acad. Sci.
695:278-284 (citing constitutive secretion of neurotransmitter as unaddressed issue). Thus, there is also a need for sources of neural progenitor cells which produce neurotransmitters via a feedback control mechanism.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery that porcine neural cells and, in particular, porcine embryonic neural cells isolated during certain stages of gestational development, when transplanted into the brain of a xenogeneic subject, promote the development of efferent connections between graft cells and distant brain targets in the host subject and receive afferent input from the host. Moreover, the porcine neural cells of the invention provide a source of neurotransmitters which are regulated by feedback control systems.
Accordingly, the instant invention pertains to a porcine neural cell or an isolated population of porcine neural cells suitable for transplantation into a xenogeneic subject, particularly a human subject. The porcine neural cell, in unmodified form, has at least one antigen on the cell surface which is capable of stimulating an immune response against the cell in a xenogeneic subject, for example, a human. The antigen on the surface of the porcine neural cell is altered to inhibit rejection of the cell when introduced into a xenogeneic subject. In one embodiment, the cell surface antigen which is altered is an MHC class I antigen. This MHC class I antigen can be contacted, prior to transplantation into a xenogeneic subject with at least one MHC class I antibody, or a fragment or derivative thereof, which binds to the MHC class I antigen on the cell surface but does not activate complement or induce lysis of the cell. One example of an MHC class I antibody is an MHC class I F(ab′)
2
fragment, such as an MHC class I F(ab′)
2
fragment of a monoclonal antibody PT85.
Particularly preferred porcine neural cells for use in treatment of human neurological deficits due to neurodegenerative diseases are mesencephalic, striatal, and cortical cells. Typically, these neural cells are obtained from embryonic pigs during selected stages of gestational development. For example, it has been determined that embryonic ventral mesencephalic cells obtained from an embryonic pig between about days 20 and 30, more preferably about days 24 and 30, and still more preferably about days 25 and 28, and yet more preferably about days 26 and 28, and most preferably about day 27 of gestation are suitable for transplantation into xenogeneic subjects, particularly human subjects. Similarly, it has been determined that porcine striatal cells obtained from an embryonic pig between about days 20 and 50, more preferably about days 30 to 40, and most preferably about days 31 and 38 are suitable for transplantation into xenogeneic subjects. In one embodiment, the striatal cells are obtained from a gan
Dinsmore Jonathan
Isacson Ole
Lahive & Cockfield LLP
Mandragouras Esq. Amy E.
Saoud Christine J.
The McLean Hospital Corporation
Turner Sharon L
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