Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Reexamination Certificate
1999-09-29
2001-04-10
Schwartzman, Robert A. (Department: 1636)
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
C435S320100, C435S325000, C536S023100, C536S023500, C536S024100
Reexamination Certificate
active
06214620
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention is related to the field of cellular excitability. In particular it is related to the disorders in cellular excitability which lead to epilepsy, cardiac arrhythmias, and intractable pain.
BACKGROUND OF THE INVENTION
Excessive cellular excitability underlies a variety of common, often lethal diseases, ranging from epilepsy to cardiac ventricular arrhythmias. Conventional therapeutic efforts to suppress excitability in such disorders center around pharmacological block of selected ion channels, mechanical disruption of an irritable focus, or devices such as pacemakers or defibrillators. Drug block of ion channels, while sometimes effective, is plagued by side effects attributable to the systemic administration of drugs needed only in small areas of the body. Mechanical disruption of epileptic or arrhythmic foci is traumatic, irreversible and often ineffective. Implantable devices designed to terminate hyperexcitation are expensive, and are activated only after the seizure has begun. Thus there is a need in the art for additional means of treating hyperexcitability which are more effective, less invasive, and less expensive.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide methods for altering the excitability of cells.
It is another object of the present invention to provide methods for altering the excitability of cells, such as those involved in epilepsy, cardiac arrhythmia, and intractable pain.
These and other objects of the invention are achieved by providing a method of altering cellular excitability. A genetic construct is delivered to a cell. The genetic construct comprises an inducible promoter and a sequence encoding an ion channel. The inducible promoter regulates transcription of the sequence. The inducible promoter is regulated by an externally controllable stimulus. Thus, the excitability of the cell is regulated by the externally controllable stimulus.
According to another embodiment of the invention, a method is provided for altering cellular excitability. A genetic construct is delivered to a neuronal cell. The genetic construct comprises an ecdysone-inducible promoter and a sequence encoding a potassium ion channel. The inducible promoter regulates transcription of the sequence. The inducible promoter is regulated by muristerone A and similar ligands such as ponasterone. Thus, the excitability of the neuronal cell is regulated by muristerone A.
These and other embodiments provide the art with new methods and tools for counteracting pathological hyperexcitability of cells.
REFERENCES:
Wang et al., J. Neurosci. 17: 882-890, The seizure locus encodes the Drosophila homolog of the HERG potassium channel, Feb. 1997.*
Zhao et al., J. Neurosci. 15: 1406-1418, Functional expression of Shaker K+ channles in cultured Drosophila “Giant” neurons derived from Sh cDNA transformants: distinct properties, distribution, and turnover, Feb. 1995.*
Yang et al., Proc. Natl. Acad. Sci. 87: 9568-9572, In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment, Dec. 1990.*
Gossen et al., Trends Biochem. Sci. 18: 471-475, Control of gene activity in higher eukaryotic cells by prokaryotic regulatory elements, Dec. 1993.*
Wang et al., Human Gene Therapy 7: 1743-1756, Construction of human factor IX expression vectors in retroviral vector frames optimized for muscle cells, Sep. 1996.*
Blomer et al., J. Virology 71: 6641-6649, Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector, Sep. 1997.*
Lachmann et al., Mol. Medicine Today 3: 404-411, The use of herpes simplex virus-based vectors for gene delivery to the nervous system, Sep. 1997.*
Han et al. “Expression of noninactivating K+ channels(aK5.1) into Aplysia neuron using heat-shock inducible promoters and the study of its effect on neuronal activities” Fourth Meeting of the Asian-Pacific Society for Neurochemistry and the Annual Meeting of the Korean Society for Neuroscience; Seoul, Korea; Jun. 24-26, 1998, vol. 70, No. Suppl. 2, p. S20.
No et al. “Ecdysone-Inducible Expression in Mammalian Cells and Transgenic Mice” Proceedings of the National Academy of Sciences, USA, vol. 93, 1996, pp. 3346-3351.
Nuss et al. “Reversal of potassium channel deficiency in cells from failing hearts by adenoviral gene transfer: A prototype for gene therapy for disorders of cardiac excitability and contractility.” Gene Therapy 1996, vol. 3, No. 10, 1996 pp. 900-912.
Hebert “General principles of the structure of ion channels” American Journal of Medicine, Jan. 1998, vol. 104, No. 1, Jan. 1998 pp. 87-98.
Johns et al. “Suppression of neuronal and cardiac transient outward currents by viral gene transfer of dominant-negative Kv4.2 constructs” Journal of Biological Chemistry Dec. 12, 1997, vol. 272, No. 50 pp. 31598-31603.
Gingrich et al. “Inducible gene expression in the nervous system of transgenicmice” Annual Review of Neuroscience Annual Review of Neuroscience. 1998 Annual Review Inc. P.O. Box 10139, 4139 El Camino Way, Pal Alto, California 94306, vol. 21, 1998, pp. 377-405.
Johns et al. “Inducible genetic suppression of neuronal excitability” Journal of Neuroscience Mar. 1, 1999, vol. 19, No. 5, Mar. 1, 1999, pp. 1691-1697.
Johns David C.
Marban Eduardo
Banner & Witcoff , Ltd.
Davis Katharine F
Schwartzman Robert A.
The Johns Hopkins University
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