Methods and systems for noninvasive control of brain cells and related vectors and compositions

{
  "publication_number": "US2019175763A1",
  "country": "US",
  "kind": "A1",
  "title": "Methods and systems for noninvasive control of brain cells and related vectors and compositions",
  "abstract": "Provided herein are methods, systems, and related vectors and compositions allowing for noninvasive control of neural circuits. In particular, the methods and systems herein described utilize acoustically targeted chemogenetics to achieve a noninvasive neuromodulation in specifically selected cell-types among spatially selected brain regions.",
  "claims": [
    "1. A method to control a target brain cell activity with respect to a target neural circuit of an individual, the method comprising applying focused ultrasound to a target brain region of the individual the target brain region comprising the target brain cell, and systemically administering to the individual an effective amount of microbubble contrast agents, the applying focused ultrasound and the systematically administering microbubble contrast agent is performed to induce transient blood-brain barrier opening at the target brain region, before, simultaneously, in combination with, or after the applying focused ultrasound, systemically administering to the individual an effective amount of an expression vector configured to enter the brain at the transient blood-brain barrier opening and to specifically deliver and express in the target brain cell a gene encoding a chemogenetic protein under control of a promoter configured to be active in the target brain cell, the chemogenetic protein configured to activate or inhibit the target brain cell activity following binding with a corresponding chemical actuator or metabolite thereof, the applying, the systemically administering an effective amount of microbubble contrast agents, and the systemically administering an effective amount of an expression vector, performed to deliver and express the gene encoding a chemogenetic protein in a controlled percentage population of the target brain cell in the target brain region to obtain a chemogenetically treated target brain region in which target brain cells of the controlled percentage population comprise the chemogenetic protein and systemically administering to the individual the corresponding chemical actuator, to allow binding of the corresponding chemical actuator or a metabolite thereof with the chemogenetic protein in the target brain cells of the controlled population of the chemogenetically treated target brain region, and activation or inhibition of the target brain cell activity. 2. The method of claim 1, wherein the controlled percentage population is at least 20% of the target brain cell of the target brain region. 3. The method of claim 1, wherein the controlled percentage population is at least 40% of the target brain cell of the target brain region. 4. The method of claim 1, wherein the controlled percentage population is at least 50% of the target brain cell of the target brain region. 5. The method of claim 1, wherein the systemically administering an effective amount of a microbubble contrast agent, the systemically administering an effective amount of an expression vector and/or the systemically administering to the individual the corresponding chemical actuator, is performed by intravenous injection. 6. The method of claim 1, wherein the applying focused ultrasound is performed at a frequency of 100 kHz to 100 MHz. 7. The method of claim 1, wherein the applying focused ultrasound is performed at a frequency of 0.2 to 1.5 mHz. 8. The method of claim 1, wherein the applying focused ultrasound is performed within an ultrasound having a mechanical index in a range between 0.2 and 0.6. 9. The method of claim 1, wherein the expression vector is a viral vector. 10. The method of claim 9, wherein the expression vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, and AAV-DJ. 11. The method of claim 1, wherein the chemogenetic protein is DREADD, PSAM, and/or TrpV1. 12. The method of claim 11, wherein the chemogenetic protein is selected from the group consisting of hM2Di, hM4Di, hM1Dq, hM3Dq and hM5Dq. 13. The method of claim 1, wherein the chemical actuator is selected from clozapine-N-oxide, clozapine, compound 21, and perlapine. 14. The method of claim 1, wherein the target region has a size in a range between 1 and 10 mm. 15. The method of claim 1, wherein the target region is selected from the group consisting of hippocampus, basal ganglia, arcuate nucleus, dorsal striatum, thalamus, medial prefrontal complex, and dorsal palidum. 16. The method of claim 1, wherein the microbubble has an average diameter between 1 and 5 microns. 17. The method of claim 16, wherein the microbubble contrast agent is in a concentration of 1.2E7-1.2E9 per kg of body weight of the individual. 18. The method of claim 1, the administering of the microbubble contrast agent is performed in combination with the administering the expression vectors. 19. The method of claim 1, wherein the expression vector is in a concentration between 2E13-2E14 viral particles per kilogram of body weight of the subject. 20. The method of claim 1, wherein the administering of the chemical actuator is performed at least one week after the administrating of the expression vector and the applying of focused ultrasound. 21. A system to control a target brain cell activity with respect to a neural circuit, the system comprising: an expression vector configured to enter the brain at the transient blood-brain barrier opening and to specifically deliver and express in the target brain cell a gene encoding a chemogenetic protein under control of a promoter configured to be active in the target brain cell, the chemogenetic protein configured to activate or inhibit the target brain cell activity following binding with a corresponding chemical actuator or metabolite thereof the corresponding chemical actuator configured to directly or indirectly convert the chemogenetic protein in an operative state; and a microbubble contrast agent for simultaneous combined or sequential use in the method of claim 1. 22. The system of claim 21, wherein the expression vector is a viral vector. 23. The system of claim 22, wherein the expression vector is selected from the group consisting of AAV1, AAV2, AAV3, AAV5, AAV6, AAV7, AAV8, AAV9, AAV11, and AAV-DJ. 24. The system of claim 21, wherein the chemogenetic protein is DREADD, PSAM, and/or TrpV1. 25. The system of claim 24, wherein the chemogenetic protein is selected from the group consisting of hM2Di, hM4Di, hM1Dq, hM3Dq and hM5Dq. 26. The system of claim 21, wherein the chemical actuator is selected from clozapine-N-oxide, clozapine, compound 21, and perlapine. 27. The system of claim 21, wherein microbubbles contain an encapsulated gas and a shell of lipid or protein. 28. The system of claim 27, wherein the encapsulated gas is perfluren or C3F8. 29. The system of claim 28, wherein the contrast agent is selected from The Definity®, Sonovue®, Optison®, and USphere®. 30. A method to modify a target behavior or physiological function of an individual associated with a target brain cell activity with respect to a neural circuit of the individual, the method comprising applying focused ultrasound to a target brain region of the individual the target brain region comprising the target brain cell, and systemically administering to the individual an effective amount of microbubble contrast agents, the applying focused ultrasound and the systematically administering microbubble contrast agent is performed to induce transient blood-brain barrier opening at the target brain region. before, simultaneously, in combination with, or after the applying focused ultrasound, systemically administering to the individual an effective amount of an expression vector configured to enter the brain at the transient blood-brain barrier opening and to specifically deliver and express in the target brain cells a gene encoding a chemogenetic protein under control of a promoter configured to be active in the target brain cell, the chemogenetic protein configured to activate or inhibit the target brain cell activity following binding with a corresponding chemical actuator or metabolite thereof to modify the target behavior or physiological function of an individual, the systemically administering an effective amount of a microbubble contrast agent and the systemically administering an effective amount of an expression vector are performed to deliver and express the gene encoding a chemogenetic protein in a controlled percentage population of the target brain cell in the target brain region associate with the target behavior or physiological function, and to obtain a chemogenetically treated target brain region in which the controlled percentage population of the target brain cell comprises the chemogenetic protein; systemically administering to the individual the corresponding chemical actuator, to allow binding of the corresponding chemical actuator or a metabolite thereof with the chemogenetic protein in the controlled percentage population of the target brain cell of the chemogenetically treated target brain region, to modify the target behavior or physiological function of the individual. 31. A system to modify a target behavior or physiological function of an individual associated with a target brain cell activity with respect to a neural circuit of the individual, the system comprising an expression vector configured to enter the brain at a transient blood-brain barrier opening and to specifically deliver and express in the target brain cells a gene encoding the chemogenetic protein under control of a promoter configured to be active in the target brain cell, a chemical actuator configured to activate the chemogenetic protein through direct binding to the chemogenetic protein of the chemical actuator or of a metabolite thereof, and the microbubble contrast agent for simultaneous, combined or sequential use in the method to modify a target behavior or physiological function of an individual of claim 30. 32. A method for treating or preventing in an individual a condition associated with a target brain cell activity with respect to a neural circuit of the individual, the method comprises applying focused ultrasound to a target brain region of the individual the target brain region comprising the target brain cell, and systemically administering to the individual an effective amount of microbubble contrast agents, the applying focused ultrasound and the systematically administering microbubble contrast agent is performed to induce transient blood-brain barrier opening at the target brain region, before, simultaneously, in combination with, or after the applying focused ultrasound, systemically administering to the individual an effective amount of an expression vector configured to enter the brain at the transient blood-brain barrier opening and to specifically deliver and express in the target brain cells a gene encoding a chemogenetic protein under control of a promoter configured to be active in the target brain cell, the chemogenetic protein configured to activate or inhibit the target brain cell activity following binding with a corresponding chemical actuator or metabolite thereof to treat or prevent the condition in the individual, the applying, the systemically administering an effective amount of microbubble contrast agents and the systemically administering an effective amount of an expression vector are performed to deliver and express the gene encoding a chemogenetic protein in a controlled percentage population of the target brain cell in the target brain region, the controlled percentage population associated with the treating or preventing of the condition in the individual, and to obtain a chemogenetically treated target brain region in which target brain cells of the controlled percentage population comprise the chemogenetic protein; systemically administering to the individual the corresponding chemical actuator, to allow binding of the corresponding chemical actuator or a metabolite thereof with the chemogenetic protein in the target brain cells of the controlled population of the chemogenetically treated target brain region, thus treating or preventing the condition in the individual. 33. The method of claim 32, wherein the controlled percentage population is at least 40% of the target brain cell of the target brain region. 34. The method of claim 32, wherein the controlled percentage population is at least 50% of the target brain cell of the target brain region. 35. A system for treating or preventing in an individual a condition associated with a target brain cell activity with respect to a neural circuit of the individual, the method comprises a pharmaceutical composition comprising the expression vector configured to express the gene encoding for the chemogenetic protein in a target brain cell and a pharmaceutically acceptable vehicle, a pharmaceutical composition comprising a chemical actuator configured to activate the chemogenetic protein through direct binding to the chemogenetic protein of the chemical actuator or of a metabolite thereof, for combined or sequential use in the method to treat or prevent in an individual a neurological condition of claim 32."
  ],
  "cpc": [
    "A61K 48/0058",
    "A01K 2217/206",
    "A01K 2227/105",
    "A61K 38/1709",
    "A61K 48/0016",
    "A61K 48/0025",
    "A61K 48/0066",
    "A61K 48/0075",
    "A61K 48/0083",
    "A61K 9/0019",
    "A61M 37/00",
    "A61N 2007/0021",
    "A61N 2007/003",
    "A61N 2007/0039",
    "A61N 7/00",
    "A61P 21/00",
    "C12N 15/113",
    "C12N 2750/14143",
    "C12N 2830/008"
  ],
  "assignees": [
    "CALIFORNIA INST OF TECHN"
  ],
  "filing_date": "2018-12-07",
  "publication_date": "2019-06-13",
  "priority_date": "2017-12-07",
  "application_number": "US-201816213991-A",
  "family_id": "66734897"
}