Manipulation of neuronal ion channels

Abstract

The present invention provides compositions and methods for the manipulation of ion channels. For example, the present invention relates to Parkinson's and other neurological diseases and conditions, and treatments thereof. In particular, the present invention provides methods of decreasing pathophysiological high frequency neuronal bursts of Parkinson's and other neurological diseases and conditions. Methods of the present invention comprise decreasing Kv3 ion channel activity in fast-spiking neurons, including by decreasing activity of a Kv3.4 protein and by specifically targeting a Kv3.4 protein with an inhibitor.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 761,557, (allowed), filed: Jan. 21, 2004, which claims priority to U.S. Provisional Patent Application Ser. No. 60 / 441,375, filed: Jan. 21, 2003, both of which are herein incorporated by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The present application was made with government support under grant number PO1 ns-26473 from the National Institutes of Health National Institute of Neurological and Stroke Disease. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention provides compositions and methods for the manipulation of ion channels. For example, the present invention relates to Parkinson's and other neurological diseases and conditions, and treatments thereof. In particular, the present invention provides methods of decreasing pathophysiological high frequency neuron...

AI Technical Summary

Benefits of technology

[0017]The present invention relates to Parkinson's and other neurological diseases and conditions, and treatments therefore. In particular, the present invention provides methods of decreasing pathophysiological high frequency neuronal bursts of Parkinson's and other neurological diseases and conditions.

[0020]In yet other embodiments, the present invention provides methods of inhibiting the ability of a fast-spiking neuronal cell to discharge at high rates, comprising transforming the cell with a vector encoding an siRNA directed against a gene encoding a Kv3.4 protein (e.g., Kv3.4a) and capable of expression in the cell, such that expression of the Kv3.4 protein is decreased, and the ability of the neuronal cell to discharge at high rates is inhibited.

[0032]The Kv3 subfamily of K+ channels are characterized by positively shifted voltage dependencies and very fast deactivation rates. Thus, all Kv3 currents activate relatively fast at voltages more positive than −10 mV. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height. The activation voltage and fast deactivation rates are believed to allow these channels to help repolarize action potentials fast without affecting the threshold for action potential generation. The fast deactivating current generates a quick recovery after hyperpolarization, thus maximizing the rate of recovery of Na+ channel inactivation without contributing to an increase in the duration of the refractory period. The short spike duration and rapid deactivation of the Kv3 currents after spike repolarization maximize the quick recovery of resting conditions after an action potential.

[0033]Several neurons in the mammalian central nervous system have incorporated into their repertoire of voltage-dependent conductances a relatively large number of Kv3 channels to enable repetitive firing at high frequencies, which ability crucially depends on the specific properties of Kv3 channels and their impact on excitability. Thus, the properties of the Kv3 channels are believed to contribute to the ability of neurons to fire at high frequencies and to help regulate the fidelity of synaptic transmission.

[0094]The terms “specific binding” or “specifically binding” when used in reference to the interaction of an antibody and a protein or peptide means that the interaction is dependent upon the presence of a particular structure (i.e., the antigenic determinant or epitope) on the protein; in other words the antibody is recognizing and binding to a specific protein structure rather than to proteins in general. For example, if an antibody is specific for epitope “A,” the presence of a protein containing epitope A (or free, unlabelled A) in a reaction containing labeled “A” and the antibody will reduce the amount of labeled A bound to the antibody.

Problems solved by technology

Parkinson's disease is caused by the degeneration of the pigmented neurons in the Substantia Nigra of the brain, resulting in decreased dopamine availability.

Treatment with levodopa does not, however, prevent the progressive changes of the brain typical of Parkinson's disease.

The drug may also produce side effects in some people, due to its change to dopamine before reaching the brain.

Thus, patients experienced debilitating side effects, including severe nausea and vomiting.

Most effective in the control of tremor, these drugs may be contraindicated in certain older patients since they tend to cause confusion and hallucination.

Unfortunately, all of the medications currently available exhibit undesirable side effects.

As with any surgical procedure, there are risks involved.

The most serious is the possibility of stroke; other risks include partial loss of vision, speech and swallowing difficulties, and confusion, as well as the general risks associated with surgery.

All of the treatments described above suffer from drawbacks, some serious, which debilitate the patient and compromise the quality of life.

Moreover, none of these treatments provide a cure for the disease.