# US 10,117,776 B2 · Devices and methods for treatment of ocular disorders through delivery of therapeutic nucleic acids

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- Number: US 10,117,776 B2
- Document ID: US10117776B2
- Status: Granted
- Kind: B2
- Application number: 15/335,324
- Filed: 2016-10-26
- Published: 2017-05-04
- Granted: 2018-11-06
- Earliest claimed: 2015-10-30
- Assignees: Doheny Eye Institute
- Applicants: Doheny Eye Institute
- Inventors: Chee Hian Tan
- Web page: https://patentgrep.com/patent/US10117776B2

## CPC

- A61F 9/00781: {Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment (drainage implants in general A61M27/002)}
- A61B 3/16: for measuring intraocular pressure, e.g. tonometers
- A61F 9/0008: {Introducing ophthalmic products into the ocular cavity or retaining products therein (putting in contact lenses A61F9/0061; introducing or retaining media in cavities of the body in general A61M31/00)}
- A61F 9/0017: {implantable in, or in contact with, the eye, e.g. ocular inserts}
- A61F 9/0026: {Ophthalmic product dispenser attachments to facilitate positioning near the eye}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 41/0047: {Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent}
- A61N 1/0424: {Shape of the electrode}
- A61N 1/0472: {Structure-related aspects}
- A61N 1/32: alternating or intermittent currents {(applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02)}
- A61N 1/327: {for enhancing the absorption properties of tissue, e.g. by electroporation}
- A61F: FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS (dental prosthetics A61C)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## Abstract

Several embodiments disclosed herein relate to the delivery of therapeutic nucleic acids to an ocular tissue in order to provide a therapeutic effect to reduce symptoms of or otherwise alleviate an ocular disorder. In particular embodiments, plasmid DNA is delivered to the cells of the trabecular meshwork in order to ameliorate increasing intraocular pressure. Devices and systems to accomplish this delivery are also disclosed.

## Claims

### Claim 1

A device for generating and applying an electrical field to an ocular target tissue, comprising:
a first arcuate housing in which is positioned a plurality of positive electrodes;
a second arcuate housing in which is positioned a plurality of negative electrodes,
wherein the first arcuate housing and the second arcuate housing are configured to be coupled to form on a same plane a single ovoid-shaped structure, wherein the first and second arcuate housings are adjustable with respect to one another to adjust an outer perimeter of the single ovoid-shaped structure to a desired dimension, said desired dimension corresponding to the shape of an outer surface of an eye of a subject; and
a control module configured to accept user input related to a percentage of the plurality of positive and negative electrodes to be activated on the single ovoid-shaped structure during the application of the electrical field to a specific ocular target tissue.

### Claim 2 (depends on 1)

The device of claim 1, wherein the plurality of positive and plurality of negative electrodes are equal in number.

### Claim 3 (depends on 1)

The device of claim 1, wherein the ocular target tissue is the trabecular meshwork and the electrical field is applied at a voltage between 100 mV and 100 V, wherein the electric field is pulsed between 1 and 20 pulses, wherein the pulses are applied for a duration of between 0.5 and 10 milliseconds per pulse, and wherein the pulses are separated by an interval of between about 20 to 150 milliseconds.

### Claim 4 (depends on 1)

The device of claim 1, further comprising an injection system, comprising:
a first syringe configured to deliver a therapeutic agent to an anterior chamber of the eye of the subject; and
a second syringe configured to withdraw aqueous humor from the anterior chamber of the eye of the subject.

### Claim 5 (depends on 4)

The device of claim 4, wherein the therapeutic agent comprises nucleic acid, and wherein the device is configured to deliver the therapeutic agent in a volume of about 10 to about 1000 microliters, and at a concentration between about 10 micrograms nucleic acid per milliliter to 5000 micrograms nucleic acid per milliliter.

### Claim 6 (depends on 4)

The device of claim 4, wherein the volume of aqueous humor withdrawn is equivalent to the volume of therapeutic agent delivered, and the withdrawal of aqueous humor is performed prior to delivery of the therapeutic agent.

### Claim 7 (depends on 4)

The device of claim 4, wherein the device is configured to deliver the therapeutic agent at a rate between about 0.1 microliters per minute and about 100 microliters per minute.

### Claim 8 (depends on 4)

The device of claim 4, wherein the device is configured to deliver the therapeutic agent at a pressure between about 10 and about 40 mm of mercury.

### Claim 9 (depends on 4)

The device of claim 4, wherein the therapeutic agent comprises a polynucleotide encoding lysyl oxidase-like 1 (LOXL1), CYP1B1, myocilin, TGF-beta latency-associated peptide (LAP), prostaglandin F synthase, C3 transferase, caldesmon or variants thereof.

### Claim 10 (depends on 4)

The device of claim 4, further comprising a pressure transducer configured to assess an intraocular pressure of the anterior chamber.

### Claim 11 (depends on 10)

The device of claim 10, wherein one or more of a volume, a concentration, a rate, a frequency, or a pressure of the delivery of the therapeutic agent is selected based on the assessed intraocular pressure.

### Claim 12 (depends on 1)

The device of claim 1, wherein the first arcuate housing forms a first arcuate portion of the single ovoid-shaped structure and the second arcuate housing forms a second arcuate portion of the single ovoid-shaped structure.

### Claim 13

A device for generating and applying an electrical field to an ocular target tissue, comprising:
a first arcuate housing in which is positioned at least one positive electrode;
a second arcuate housing in which is positioned at least one negative electrode,
wherein the first arcuate housing and the second arcuate housing are configured to be coupled to form on a same plane a single ovoid-shaped structure, wherein the first and second arcuate housings are adjustable with respect to one another to adjust on the same plane an outer perimeter of the single ovoid-shaped structure to a desired dimension, said desired dimension corresponding to the shape of an outer surface of an eye of a subject.

### Claim 14 (depends on 13)

The device of claim 13, wherein the first arcuate housing comprises a plurality of positive electrodes, and wherein the second arcuate housing comprises a plurality of negative electrodes.

### Claim 15 (depends on 14)

The device of claim 14, wherein the plurality of positive and plurality of negative electrodes are equal in number.

### Claim 16 (depends on 13)

The device of claim 13, further comprising a control module configured to accept user input related to a percentage of the plurality of positive and negative electrodes to be activated during the application of the electrical field to a specific ocular target tissue.

### Claim 17 (depends on 13)

The device of claim 13, wherein the device is configured to apply an electrical field focused on the trabecular meshwork of the eye of the subject.

### Claim 18 (depends on 13)

The device of claim 13, wherein the device is configured to apply an electrical field focused on the ciliary body of the eye of the subject.

### Claim 19 (depends on 13)

The device of claim 13, wherein the device is configured to allow delivery of a therapeutic agent to a specific ocular target tissue, wherein the therapeutic agent comprises a plasmid.

### Claim 20 (depends on 13)

The device of claim 13, wherein the first arcuate housing forms a first arcuate portion of the single ovoid-shaped structure and the second arcuate housing forms a second arcuate portion of the single ovoid-shaped structure.

### Claim 21

A device for generating and applying an electrical field to an ocular target tissue, comprising:
a first arcuate housing in which is positioned at least one positive electrode;
a second arcuate housing in which is positioned at least one negative electrode,
wherein the first arcuate housing and the second arcuate housing are configured to be coupled to form on a same plane a single ovoid-shaped structure, wherein the first and second arcuate housings are adjustable with respect to one another to adjust on the same plane an outer perimeter of the single ovoid-shaped structure to a desired dimension, said desired dimension corresponding to the shape of an outer surface of an eye of a subject; and
an injection system for delivery of a therapeutic agent to a specific ocular target tissue for the treatment of elevated intraocular pressure.

### Claim 22 (depends on 21)

The device of claim 21, wherein the therapeutic agent comprises a polynucleotide encoding lysyl oxidase-like 1 (LOXL1), CYP1B1, myocilin, TGF-beta latency-associated peptide (LAP), prostaglandin F synthase, C3 transferase, caldesmon or variants thereof.

### Claim 23 (depends on 21)

The device of claim 21, wherein the first arcuate housing forms a first arcuate portion of the single ovoid-shaped structure and the second arcuate housing forms a second arcuate portion of the single ovoid-shaped structure.