# Patent

## Title
Methods for modulating cell function

## Abstract

Methods for modulating nerve function are disclosed. An example method for modulating nerve function may include providing a transgene including a neuron-specific promoter and a gene encoding a light-sensitive protein, delivering the transgene to a body tissue including one or more target neurons, implanting a light source adjacent to the cell bodies of the one or more target neurons, and emitting light from the light source. Light may be exposed to the cell bodies of the one or more target neurons and may cause a conformational change in the light-sensitive protein.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. §119 to U.S. Provisional Application Ser. No. 61/578,770, filed Dec. 21, 2011, the entirety of which is incorporated herein by reference.


TECHNICAL FIELD
The present disclosure pertains to medical devices and methods for modulating cell function. More particularly, the present disclosure pertains to methods for modulating renal nerve function.
BACKGROUND
A wide variety of diagnostic and/or medical treatment methods are known. Of the known methods, each has certain advantages and disadvantages. There is an ongoing need to provide alternative diagnostic and/or medical treatment methods.
BRIEF SUMMARY
This disclosure provides alternative methods for modulating cell function. An example method may include a method for modulating nerve function to treat autonomic imbalances. The method may include providing a transgene including a neuron-specific promoter and a gene encoding a light-sensitive protein, delivering the transgene to a body tissue including one or more target neurons, implanting a light source adjacent to the cell bodies of the one or more target neurons, and emitting light from the light source. Light may be exposed to the cell bodies of the one or more target neurons and may cause a conformational change in the light-sensitive protein.
Another example method may include a method for treating hypertension. The method may include providing a viral vector carrying a transgene. The transgene may include a neuron-specific promoter and a gene encoding a nerve modulation protein. The method may also include delivering the viral vector to a body tissue of a patient. The body tissue may include one or more neurons. The method may also include infecting the neurons with the viral vector, implanting a light source adjacent to the cell bodies of the one or more neurons and emitting light from the light source. Light may be exposed to the cell bodies of the one or more neurons and may reduce blood pressure in the patient.
Another example method may be a method for cell modulation. The method may include providing a viral vector carrying a transgene. The transgene may include a tissue-specific promoter and a gene encoding a cell modulation protein. The method may also include delivering the viral vector to a body tissue adjacent to one or more target cells, infecting the target cells with the viral vector, and implanting a light source adjacent to a portion of the target cells, and emitting light from the light source. Light may be exposed to the target cells and may cause a structural change in the cell modulation protein.
Another example method for treating hypertension may include providing a viral vector carrying a transgene. The transgene may include a light-sensitive promoter that drives expression of a first gene encoding a nerve modulation protein and a second gene encoding an enzyme that convert a non-toxic form of a toxin to a toxic form of the toxin. The method may also include delivering the viral vector to a body tissue of a patient. The body tissue may include one or more neurons. The method may also include infecting the neurons with the viral vector, implanting a light source adjacent to the cell bodies of the one or more neurons, and emitting light of a first wavelength from the light source. The light of the first wavelength may be exposed to the cell bodies of the one or more neurons and may drive expression of the first gene and the second gene. The method may also include emitting light of a second wavelength from the light source. Light of the second wavelength may reduce blood pressure in a patient.
Also disclosed is a system for nerve cell modulation. The system may include a light source implantable within a patient (e.g., within the epidural space). The system may also include one or more sensors may be implantable within the patient. The system may also include an integration member that integrates data collected by the sensors and alters emission of light from the light source in response to the data.
The above summary of some embodiments is not intended to describe each disclosed embodiment or every implementation of the present invention. The Figures, and Detailed Description, which follow, more particularly exemplify these embodiments.



BRIEF DESCRIPTION OF THE DRAWINGS
The invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings, in which:
FIG. 1 is a plan overview of an example system for modulating cell function; and
FIG. 2 is a side view of a portion of an example light source.



While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
DETAILED DESCRIPTION
For the following defined terms, these definitions shall be applied, unless a different definition is given in the claims or elsewhere in this specification.
All numeric values are herein assumed to be modified by the term “about,” whether or not explicitly indicated. The term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the terms “about” may include numbers that are rounded to the nearest significant figure.
The recitation of numerical ranges by endpoints includes all numbers within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).
As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
Certain treatments may require the temporary or permanent interruption or modification of select nerve function. One example treatment is renal sympathetic nerve ablation. The ablation procedure typically includes advancing an ablation catheter or device through the vasculature to the renal artery. The clinician can then activate the ablation electrode or transducer to ablate tissue including renal nerves that tend to surround the renal artery. Ablation of renal nerves, while looking like a promising option for treating hypertension, may have some limitations. For example, the ablation process may cause some damage to the endothelial layer and/or the smooth muscle layer of the renal artery. In addition, the ablation process is “permanent” and generally not reversible or adjustable.
Some studies have indicated that ablation of renal sympathetic nerves contributes to reduced blood pressure in patients with hypertension. While not wishing to be bound by theory, the mechanism for the reduction of blood pressure is believed to be due to afferent nerves. In other words, it is believed that disruption and/or ablation of the afferent renal nerves leads to a reduction in blood pressure. The nerve endings for these afferent renal nerves are located at or adjacent the renal pelvis. The cell bodies of the afferent renal nerves are located in the ipsilateral dorsal root ganglion from about T6 to L4 vertebrae (with the predominance being from about T12 to L3 vertebrae).
Disclosed herein are methods for modulating cell function including, for example, modulating nerve cell function. This may include treatments for autonomic nervous system dysfunction or imbalances such as, for example, mismatched or imbalanced sympathetic and parasympathetic regulation. In at least some embodiments, the methods may relate to modulation of afferent renal nerves for the treatment of hypertension. However, this is not intended to be limiting as other methods are contemplated where other nerves and/or cell types are modulated. In addition to hypertension, the methods disclosed herein may be used to treat conditions including, but not limited to, heart failure, post myocardial infarction treatment, diabetes, or the like. Moreover, the methods disclosed herein allow modulation of target neurons from a remote access site.
The methods disclosed herein may include the use of a gene construct or transgene that may be delivered to a location adjacent to a target cell. The precise form of the transgene can vary. In at least some embodiments, the transgene may include a gene promoter and a “gene of interest”, which may encode, for example, a cell modulating protein.
The promoter may be selected so that expression of the gene of interest can be limited to desired target cells. In other words, the promoter may be a tissue-specific or cell-type-specific promoter that drives expression within only selected cells. One example promoter may be the cytomegalovirus (CMV) promoter. The CMV promoter may drive expression non-selectively in neurons and glia. Another example promoter may include the neuron-specific enolase (NSE) promoter. The NSE promoter may drive expression within neurons. Another example promoter may include the melanin-concentrating hormone (MCH) promoter. The MCH promoter may drive expression within a subpopulation of neurons in the lateral hypothalamus. These are just examples. It can be appreciated that other promoters (and/or other targeting mechanisms) may be used when other (e.g., non-neuron) tissue or cells are being targeted.
Other promoters may also be used and numerous transgenes are contemplated that utilize alternative promoters. For example, promoters that are responsive to a particular stimulus (e.g., light, current or potential, and the like) may also be used. Such promoters may allow a user to selectively “turn on” expression of the gene of interest with the use of a particular stimulus. In some embodiments, the promoter may be responsive to a different stimulus than the gene of interest (e.g., when the gene of interest is responsive to a stimulus). This may include a promoter responsive to light with a first wavelength (or first range of wavelengths) and a gene of interest responsive to light with a second wavelength (or second range of wavelengths) different from the first wavelength.
The gene of interest may also vary. In at least some embodiments, the gene of interest may encode an ion channel or ion pump (e.g., sodium ion channel or pump, chloride ion channel or pump, calcium ion channel or pump, potassium ion channel or pump, proton channel or pump, or the like). In some of these and in other embodiments, the ion channel may be light-sensitive or light-responsive ion channel or pump (e.g., the channel or pump may undergo a conformational change when exposed to light). Other genes of interest may be genes that can be used to hyperpolarize cells such as neurons, depolarize cells such as neurons, block signaling within cells, enhance signaling within cells, or the like. These may include genes that encode proteins that are sensitive to external stimuli (e.g., light, current and/or potential, temperature, or the like.)
One example gene of interest that is contemplated is a gene encoding a Channelrhodopsin protein. Channelrhodopsin protein is a light-responsive ion channel that is used in a number of unicellular organisms. Genes for Channelrhodopsin may include the Channelrhodpsin-1 (ChR1) gene, Channelrhodpsin-2 (ChR2) gene, or the Volvox Channelrhodpsin (VChR1) gene. Another example gene of interest that is contemplated is a gene encoding a Halorhodopsin protein. Halorhodopsin protein is a light-sensitive chloride ion pump. Genes for Halorhodopsin may include the Halorhodopsin gene (NpHR).
Channelrhodopsin and/or Halorhodopsin may control the flow of ions into or out of the cell in response to light. This may allow the cell to be excited (and/or activated and/or potentiated and/or depolarized) or inhibited (and/or inactivated and/or attenuated and/or hyperpolarized) in response to light. For example, the Halorhodopsin protein may use the energy from light (e.g., green/yellow light or light having a wavelength of approximately 580 nm) to move chloride ions into the cell, which may cause membrane hyperpolarization. For example, the Halorhodopsin protein may undergo a structural and/or conformational change when exposed to light that causes the chloride ion pump to pump chloride ions into the cell, thereby hyperpolarizing (inactivating) the cell. Conversely, the Channelrhodopsin protein may undergo a structural and/or conformational change when exposed to light that causes ion channel to open so that ions can move out of the cell, thereby depolarizing (e.g., activating) the cell.
Other genes of interest may include Halorhodoposin gene variants such as eNpHR2.0 and eNpHR3.0, genes for light-driven proton pumps such as archaerhodopsin-3 (Arch), Mac genes, bacteriorhodopsin genes (eBR), rhodopsin-3 genes (GtR3), synapsin-1 genes, or the like. These genes may also be used as the gene of interest.
In general, the gene of interest may be used to “activate” a cell (e.g., by activating an otherwise quiescent protein) or the gene of interest may “deactivate” the cell (e.g., by deactivating an active protein within the cell). In some of these and in other embodiments, the light energy may be used to induce cell suicide. For example, the gene of interest may be a gene that encodes a light-sensitive cell death protein such that exposure to light causes the protein to kill the cell. In still other embodiments, the gene of interest may encode or produce a light-sensitive enzyme that converts, for example, a nontoxic or inactive prodrug to a toxic or active drug. In these embodiments, a clinician may be able to test the patient (e.g., measure blood pressure) and activate the enzyme when conditions are favorable. Combination approaches are also contemplated that may utilize one or more genes of interest (e.g., one gene encoding, for example, a light sensitive ion channel and another gene encoding, for example, an enzyme that may convert a pro-drug or pro-toxin into an active drug or toxin).
Based on the forgoing, some of the transgenes contemplated may include:
CMV-ChR1
CMV-ChR2
CMV-VChR1
CMV-NpHR
CMV-eNpHR2.0
CMV-eNpHR3.0
CMV-Arch
CMV-eBR
CMV-GtR3
NSE-ChR1
NSE-ChR2
NSE-VChR1
NSE-NpHR
NSE-eNpHR2.0
NSE-eNpHR3.0
NSE-Arch
NSE-eBR
NSE-GtR3
MCH-ChR1
MCH-ChR2
MCH-VChR1
MCH-NpHR
MCH-eNpHR2.0
MCH-eNpHR3.0
MCH-Arch
MCH-eBR
MCH-GtR3
These are just examples. Other transgenes are contemplated. In addition, combination approaches are contemplated that utilize a plurality of genes driven by the same promoter. Alternatively, a plurality of different transgenes may be utilized together that may differ in the promoter utilized and/or the genes of interest. The transgene(s) may be constructed and maintained in a convenient form (e.g., a plasmid) using standard gene cloning techniques generally known to those with ordinary skill in the art.
In embodiments where the gene of interest encodes a light-sensitive protein, the wavelength of light that may be utilized to cause a structural and/or conformational change in the protein may vary. In some embodiments, the protein may be sensitive to a wide range of wavelengths (e.g., infrared or longer wavelengths to ultraviolet or shorter wavelength) or a more specific wavelength (e.g., across the visible spectrum).
In addition, the light-sensitive protein may return to its original structure and/or conformation when light energy is no longer provided. In other words, it may be possible to selectively switch the protein from a first structural conformation (e.g., “off”) to a second structural conformation (e.g., “on”) by exposing the protein to the appropriate light energy and then allow the protein to return to the first structural conformation (e.g., “off”) by removing the light. This may allow a clinician to selectively control the conformation of the protein by controlling light exposure. In other words, transient (rather than permanent) cell modulation can be achieved. In addition, the amount of light exposure can also be controlled. This may allow a clinician to “titrate” or customize the extent to which cell modulation takes place. In other words, it may be possible for a clinician to “turn up” the amount of light exposure when a larger response is desired (and/or in response to compensation by other body mechanisms or in response to a traumatic event such as a myocardial infarction) and the “turn down” the amount of light exposure when less response is needed. In addition, the amount of light exposure may also be used on a “temporary” or intermittent basis where light is emitted for one or more discrete periods of time.
The transgene may be incorporated into a delivery vector (e.g., a viral vector) for delivery to tissue adjacent to or otherwise including the target cells (e.g., the target neurons). This may include inserting the transgene into the genome of the virus. Alternatively, the transgene may be carried by the virus in a plasmid form or as a DNA fragment. The type of viral vector that may be utilized may vary. Some example viral vectors may include retroviruses, lentiviruses, adenoviruses, adeno-assisted viruses, herpes viruses (e.g., herpes simplex viruses), rabies viruses, pseudorabies viruses, or the like. The particular vector utilized may be replication deficient or otherwise “inactivated” so that unwanted spread of the virus to other tissues can be avoided. Other vectors may also be used including vectors that utilize ormosil or other non-viral substances.
The viruses may also be selected to further enhance the specificity of gene expression. The specificity may be at least partially receptor mediated. For example, some viruses (e.g., adeno-assisted viruses) may lead to differential infectivity between cell populations based on recognition between capsids and cell surface receptors. In some instances, adeno-assisted viruses may carry proteins or markers (e.g., capsid proteins) that bind to receptors on neurons, which may enhance specificity.
Having constructed a suitable viral vector carrying the desired transgene, the viral vector may be delivered to body tissue. This may include local injection of the viral vector, vascular introduction of the viral vector, or other delivery processes. For example, if the target cells are afferent renal nerve endings, the viral vector may be delivered to the renal plexus where it is believed that the viral vector can pass through the wall of the membrane and reach the nerve endings of the afferent renal nerves. There, the virus may be taken up by the neurons and transported to the cell bodies. One example method for delivering the viral vector to the renal plexus may include directly injecting the viral vector into the renal plexus. Alternatively, the method may include advancing a catheter through a body lumen such as a blood vessel or the ureter. To aid in delivery, the delivery needle and/or catheter may include a sensing structure such as two or more closely spaced electrodes that are configured to monitor nerve traffic. Upon reaching the desired position, the viral vector may be injected through the catheter (e.g., via an injection lumen or channel formed in the catheter). The catheter may include a balloon, which can be inflated to reduce backflow or loss of the viral vector at the target location.
It is contemplated that infection with the viral vector can occur over a relatively short period of time (e.g., on the order of minutes or hours). Once the viral vector has successfully infected cells, gene expression of the gene of interest can occur (e.g., if the promoter directs gene expression within the particular infected cell) and protein translation can occur. It is contemplated that sufficient protein production to effect modulation of the target cell may take place on the order of hours to a few days. In embodiments where the target cells are afferent renal nerves, the protein produced can be present in the cell membrane of the neurons at a variety of locations along the neurons include adjacent to the nerve endings as well as adjacent to the cell bodies of the neurons.
While delivery of the viral vector to afferent renal nerve endings to treat hypertension is disclosed, this is not intended to be limiting. The viral vector can be delivered to essentially any suitable target tissue including, for example, the brain, body organs, muscles, tendons, ligaments, or the like to diagnose and/or treat a number of conditions. This may include local injection of the viral vector, vascular delivery of the viral vector, absorption of the viral vector, or other suitable delivery mechanisms. The treatments may include cardiac rhythm management, angina, brain activity, organ function, pain management, growth and development, diabetes, or the like. As such, the target tissue and/or cells may be located in the heart, brain, a body organ, the spinal cord, or the like.
If the protein product of the gene is sensitive to an external stimulus (e.g., light, heat, cold, current and/or potential, or other stimuli), the method for modulation of the target cells (e.g., afferent renal neurons) may include placing a device for providing the external stimuli (e.g., a light source, a heat source, a cold source, a current and/or potential source, or other stimuli) at a convenient location so that the stimuli can reach the target cells. This may include implanting the external stimulus at a remote location. As indicated above, afferent renal nerves have cell bodies located in the dorsal root ganglion. Because of this, a device providing the external stimuli can be disposed at or near the dorsal root ganglion and provide external stimuli to the target cells. In at least some embodiments, the device for providing the external stimuli can be implanted within the epidural space between the dura matter of the spinal cord and the T6 to L4 vertebrae (or the T12 to L3 vertebrae). When so positioned, light energy can penetrate the tissue (e.g., can penetrate the dura matter, which may be about 0.27 millimeters thick or so) and reach the cell bodies of afferent renal nerves.
The device for providing external stimuli may vary. In at least some embodiments, the device may include a lead with a light source disposed at, for example, its distal end. According, to this embodiment, the lead can be implanted within the epidural space and the light source can be turned on in order to cause a change in protein product of the gene of interest. In other words, the light source can be used to cause a conformational or other change in the protein in order to modulate activity in the target cell. In other embodiments, the device may include a light guide, a fiber optic light source, a light-emitting diode (LED), or the like, or any other suitable light source. In at least some embodiments, the device for providing external stimuli may include steering capabilities and/or may have a steerable or deflectable tip. Additionally, visualization structures such as radiopaque markers or marker bands may also be used. These features may allow the device to be directed and implanted more precisely to the intended implantation target site.
A pulse generator may also be used in conjunction with the light source to provide appropriate energy to the light source. In some embodiments, the pulse generator can also be implantable (e.g., adjacent to the light source or at another convenient location) within the patient. The pulse generator may include one or more sensors that can response to certain body conditions in order to alter the energy provided to the light source. In some embodiments, the pulse generator (and/or the light source) may include a body positioning sensor that is configured to sense when the patient shifts from a sitting or laying position to a more upright position. For example, the positioning sensor may be configured to sense when a patient stands up (from a laying position) in order to attenuate light exposure and allow the body's natural barroreflexes to regulate blood pressure and, for example, avoid an unwanted drop in blood pressure (orthostatic hypotension). Accordingly, when the sensor senses a change in body position (e.g., when a patient stands up from a sitting or laying position), the amount of light emitted from the light source may be altered (e.g., reduced), which may have a corresponding effect on the protein product of the gene of interest. In some of these and in other embodiments, the pulse generator (and/or the light source) may include a blood pressure sensor that is configured to sense the blood pressure of the patient and tailor the amount of light energy provided by the light source to the current blood pressure of the patient (e.g., provide more light energy when blood pressure is elevated and/or provide less light energy when blood pressure is normal or low). Accordingly, when the sensor senses a change in blood pressure, the amount of light emitted from the light source may be altered, which may have a corresponding effect on the protein product of the gene of interest. In other words, the light emitted from the light source can be reduced or increased depending on the particular blood pressure status of the patient.
A number of alternative devices for providing external stimuli and/or alternative implantation sites for these devices are also contemplated. These devices may include, for example, a stent or implant that includes a light emitting apparatus. The light emitting apparatus may be disposed on part or all of the circumference of the stent and may be remotely powered by a separate generator (e.g., radio frequency, ultrasound, or the like). Such a device may be implanted within the renal artery. Light emitted from the stent may cause a structural and/or conformational change in the protein encoded by the gene of interest. Alternatively, a stent (lead based or leadless stent) may be implanted in the vena cava (e.g., inferior vena cava), the renal vein, or another suitable location. In still other embodiments, a cuff may be surgically placed around the renal artery and/or the nerve bundle adjacent the renal artery. The cuff may include a light source. In still other embodiments, an external power source may be used to shine focused energy to the target tissue, which may cause a structural and/or conformational change in the protein encoded by the gene of interest.
Other devices providing alternative stimuli may also be used. For example, devices that provide heat, cold, current and/or potential, or other stimuli may also be used.
FIG. 1 is a plan view illustrating an example system 10 for modulating cell function. In general, system 10 may be utilized to treat autonomic imbalances. For example, system 10 may be used to modulate afferent renal nerves for the treatment of hypertension. However, this is not intended to be limiting as system 10 may be used for other treatments or target cells including any of those disclosed herein.
In at least some embodiments, system 10 may include a light source 12. System 10 may also include one or more sensors or sensing components 14 and an integration member 16. When so provided, system 10 may be designed so that emission of light can be modulated or changed based upon feedback from the one or more sensors 14. For example, sensors 14 may collect or generate data based on the particular parameter sensed by sensors 14 (e.g., blood pressure, heart rate, body position, or the like). The data may be collected and/or processed by integration member 16, which may modulate light emission from light source 12 based on the sensed data. In some embodiments, integration member 16 may be a pulse generator or other mechanism that is generally configured to regulate emission of light from light source 12. Integration member 16 may be implantable within the patient or otherwise disposed adjacent to the patient. Alternatively, integration member 16 may include one or more machines that are designed to communicate with sensors 14 and light source 12.
A number of example sensing paradigms are contemplated in which “feedback” from sensors 14 may be communicated to integration member 16 such that light emission from light source 12 can be altered. For example, in some embodiments sensors 14 may include a blood pressure sensor. According to these embodiments, a change or deviation in blood pressure may be communicated to integration member 16 and integration member 16 may modulate light emission from light source 12. For example, if sensors 14 sense blood pressure falling below a particular level (and/or a dramatic drop in blood pressure), sensors 14 may communicate this data to integration member 16, which, in turn, may decrease or suspend light emission from light source 12. Conversely, if sensors 14 sense an increase in blood pressure, sensors 14 may communicate this data to integration member 16, which, in turn, may increase light emission from light source 12.
In some of these and in other embodiments, sensors 14 may include a body position sensor. According to these embodiments, a change in body position (e.g., a change from a laying position to a standing or upright position) may be communicated to integration member 16 and integration member 16 may modulation light emission from light source 12 (e.g., light emission may be reduced or suspended to allow the body's natural barroreflexes to regulate blood pressure and avoid an unwanted drop in blood pressure). Other sensors 14 may include movement sensors that sense activity of the patient, sensors that can detect a myocardial infarction, or the like. These sensors 14 can also communicate with integration member 16 in order to, for example, suspend or reduce light emission.
In some embodiments, sensors 14 may be implanted or placed in communication with the patient as separate leads or sensors. In other embodiments, one or more of sensors 14 may be incorporated into light source 12. Some examples of this are disclosed herein.
In use, a viral vector or transgene (as described above) may be injected into the renal plexus RP or otherwise into or adjacent to the kidney K. The viral vector may infect the nerve endings of afferent renal nerves ARN such that the gene product of the gene of interest is produced in the afferent renal nerves ARN including in the cell bodies.
A light source 12 may be implanted adjacent to target tissue. In this example, light source 12 may be implanted within the epidural space ES between the dura matter of the spinal cord SC and the vertebrae. Here, light emitted from light source may pass through the dura matter and reach the dorsal root ganglion DRG. As described herein, the cell bodies of the afferent renal nerves ARN are located in the ipsilateral dorsal root ganglion DRG. Thus, light may reach the afferent renal nerves ARN and cause a structural and/or conformational change in protein product of the gene of interest, which may modulate (e.g., hyperpolarize) the afferent renal nerves ARN.
FIG. 2 is a side view of light source 12. Here it can be seen that light source may include a number of structural features. For example, light source 12 may include a light member 18 that emits light. In addition, light source 12 may include one or more sensors 20. In some embodiments, sensors 20 may include any of those sensors disclosed herein (e.g., blood pressure sensors). In some of these and in other embodiments, sensors 20 may include other sensors such as one or more nerve sensing electrodes. These electrodes may help guide light source 12 toward target nerve tissue. In some of these and in other embodiments, sensors 20 may include a strain sensor that may provide feedback to a clinician implanting light source 12 to help avoid pushing too hard against nerves and other structures, which could cause damage.
Light source 12 may also include a steering mechanism 22. Steering mechanism 22 may be used to aid in the implantation of light source 12 (e.g., within the epidural space ES). In some embodiments, steering mechanism 22 may include a pull wire or steering wire. Other embodiments are contemplated, however, where other steering mechanism may be included.
EXAMPLES
The invention may be further clarified by reference to the following prophetic Examples, which serve to exemplify some of the preferred embodiments, and not to limit the invention in any way.
Example 1
A transgene may be made that includes the CMV promoter and a Halorhodopsin gene (NpHR).
Example 2
A transgene may be made that includes the NSE promoter and a Halorhodopsin gene (NpHR).
Example 3
A transgene may be made that includes the MCH promoter and a Halorhodopsin gene (NpHR).
Example 4
The transgene from any one of Examples 1-3 may be incorporated into the genome of an adeno-assisted virus or other virus.
Example 5
A virus from Example 4 may be injected into the renal plexus of a patient with hypertension. It is believed that the viral vector can pass through the wall of the membrane and reach the nerve endings of the afferent renal nerves. There, the virus may be taken up by the neurons and transported to the cell bodies, where Halorhodopsin protein may be produced.
A light source may be implanted within the epidural space between the dura matter of the spinal cord and the T6 to L4 vertebrae (or the T12 to L3 vertebrae). Light can be emitted from the light source. It is believed that the light will penetrate the dura matter and reach the cell bodies of afferent renal nerves, where the light can cause Halorhodopsin protein (a chloride ion pump) to undergo a conformational change and cause the chloride ion pump to pump chloride ions into the cell, thereby hyperpolarizing (inactivating) the cell. This may reduce blood pressure in the patient.
Example 6
The light source in Example 5 may include a blood pressure sensor that modulates light emission based on the blood pressure of the patient. More particularly, the blood pressure sensor may cause light emission from the light source to be reduced or “shut off” when blood pressure in the patient is normal or below normal and may cause light emission from the light source to be increased or “turned on” when blood pressure is above normal.
Example 7
The light source in either Example 5 or Example 6 may include a body position sensor that modulates light emission based on the body position of the patient. More particularly, the body position sensor may cause light emission from the light source to be reduced or “shut off” when the sensor detects a change (e.g., an abrupt change) in the position of the patient such as the patient sitting up or moving from a laying position to un upright position and allow the body's natural barroreflexes to regulate blood pressure and avoid an unwanted drop in blood pressure (orthostatic hypotension).
Example 8
A transgene may be made that includes a light sensitive promoter that drives expression of both a first gene and a second gene. The first gene may be a gene that modulates activity of a cell (e.g., inactivates or hyperpolarizes a neuron). For example, the first gene may be Halorhodopsin gene (NpHR). The second gene may be a gene that encodes an enzyme that converts an otherwise non-toxic (e.g., pro-toxin or non-toxic form of a toxin) or inactive (e.g., prodrug or inactive form of a drug) substance into a toxic or active substance.
The light sensitive promoter may be sensitive to a first wavelength (or first range of wavelengths) of light. The protein product of the first gene may also be responsive to to light of a second wavelength of light (or second range of wavelengths) different from the first wavelength.
Example 9
The transgene from Example 8 may be incorporated into the genome of an adeno-assisted virus or other virus.
Example 10
A virus from Example 9 may be injected into the renal plexus of a patient with hypertension. It is believed that the viral vector can pass through the wall of the membrane and reach the nerve endings of the afferent renal nerves. There, the virus may be taken up by the neurons and transported to the cell bodies, where the protein product of the first gene (e.g., Halorhodopsin) and the second gene may be produced.
A light source may be implanted within the epidural space between the dura matter of the spinal cord and the T6 to L4 vertebrae (or the T12 to L3 vertebrae). The light source may be configured to emit one or more wavelengths of light. Light can be emitted from the light source (e.g., light of a first wavelength). It is believed that the light will penetrate the dura matter and reach the cell bodies of afferent renal nerves, where the light can drive expression of the light sensitive promoter. This will result in expression and ultimately production of the protein products of the first gene (e.g., Halorhodopsin) and the second gene.
A second wavelength of light may be emitted from the light source. The second wavelength of light may cause a structural or conformational change in the protein product of the first gene. For example, the second wavelength of light may cause Halorhodopsin to undergo a conformational change and cause the chloride ion pump to pump chloride ions into the cell, thereby hyperpolarizing (inactivating) the cell. This may reduce blood pressure in the patient.
A clinician may measure blood pressure in the patient to determine whether or not the appropriate renal afferent nerves have been modulated by the therapy. If the clinician determines that the therapy is meeting the goals of the intervention and wishes to make the therapy “more permanent”, the clinician may administer a pro-drug or non-toxic form of a toxin to the patient. The pro-drug or non-toxic form of toxin may be converted to its active or toxic form by the enzyme produced by the second gene. It is believed that conversion (to the active or toxic form) will occur only within those cells in which the enzyme is present. Conversion of the pro-drug or non-toxic form of the toxin to the active or toxic form may kill the cells where the enzyme is present. Thus, the modulated (e.g., inactivated) cells may be killed, making the result of the modulation “permanent”.
It should be understood that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of steps without exceeding the scope of the invention. This may include, to the extent that it is appropriate, the use of any of the features of one example embodiment being used in other embodiments. The invention's scope is, of course, defined in the language in which the appended claims are expressed.

## Claims

1. A method for treating hypertension, the method comprising:
delivering a viral vector to a body tissue of a patient, wherein the body tissue includes one or more neurons;
wherein the viral vector includes a transgene, the transgene including a neuron-specific promoter and a gene encoding a nerve modulation protein, the transgene also including a second gene encoding an enzyme that converts a non-toxic form of a therapeutic agent to a toxic form;
infecting the neurons with the viral vector;
implanting a light source adjacent to the cell bodies of the one or more neurons; and
emitting light from the light source;
monitoring the patient for a change in blood pressure; and
if a change in blood pressure is observed, administering the non-toxic form of the therapeutic agent to the body tissue;
wherein the enzyme converts the non-toxic form of the therapeutic agent to the toxic form.

2. The method of claim 1, wherein emitting light from the light source causes a structural change in the nerve modulation protein and causes hyperpolarization of the neurons.

3. The method of claim 1, wherein the nerve modulation protein includes a light-sensitive ion channel.

4. The method of claim 1, wherein the nerve modulation protein includes a light-sensitive chloride ion pump.

5. The method of claim 1, wherein the viral vector includes adenovirus or an adeno-assisted virus.

6. The method of claim 1, wherein implanting a light source adjacent to the cell bodies of the one or more neurons includes implanting the light source in an epidural space of a patient.

7. The method of claim 1, wherein emitting light from the light source inactivates the one or more neurons.

8. The method of claim 1, wherein the light source includes a blood pressure sensor, wherein the method includes measuring blood pressure with the blood pressure sensor, and wherein the amount of light emitted from the light source is altered based on the measured blood pressure.

9. The method of claim 1, wherein the light source includes a body position sensor, wherein the method includes measuring body position with the body position sensor, and wherein the amount of light emitted from the light source is altered based on the measured body position.

10. The method of claim 1, wherein emitting light from the light source includes emitting light for one or more discrete time periods.

11. A method for treating hypertension, the method comprising:
providing a viral vector carrying a transgene, the transgene including a light-sensitive promoter that drives expression of a first gene encoding a nerve modulation protein and a second gene encoding an enzyme that converts a non-toxic form of a toxin to a toxic form of the toxin;
delivering the viral vector to a body tissue of a patient, wherein the body tissue includes one or more neurons;
infecting the neurons with the viral vector;
implanting a light source adjacent to the cell bodies of the one or more neurons;
emitting light of a first wavelength from the light source, wherein light of the first wavelength is exposed to the cell bodies of the one or more neurons and drives expression of the first gene and the second gene;
emitting light of a second wavelength from the light source;
measuring blood pressure in the patient; and
if a change in blood pressure is observed, administering the non-toxic form of the toxin to the body tissue;

wherein the enzyme converts the non-toxic form of the toxin to the toxic form and kills the body tissue.