Method and treatment of the eye with ultrasound

Abstract

The present disclosure provides devices, systems and methods for treating eye disorders by delivering ultrasound energy. Specifically, methods for reducing or reversing retinal ganglion nerve layer (RNFL) thinning are provided.

Description

This disclosure provides apparatus, systems, and methods for treating eye diseases by delivering ultrasound energy. Specifically, methods for reducing or reversing thinning of the retinal ganglion layer (RNFL) are provided. Abstract

Claims

WHAT IS CLAIMED IS:

1. A method of treating a subject suffering from or at risk of an eye disorder, the method comprising: providing ultrasonic energy to the limbus of an eye at an effective treatment schedule using an ultrasonic device that emits ultrasonic energy of between 0.01-5 watts of power, wherein the ultrasonic energy is concentrated at a distance between 0.01-10 mm from the tip of the sonotrode of the ultrasonic device, wherein the ultrasonic energy propagates throughout the eye, wherein the effective treatment schedule is sufficient to stimulate cell growth in the retina nerve fiber layer (RNFL) in the subject.

2. A method of increasing thickness of retina nerve fiber layer (RNFL) in a subject, the method comprising: providing ultrasonic energy to the limbus of an eye at an effective treatment schedule using an ultrasonic device that emits ultrasonic energy of between 0.01-5 watts of power, wherein the ultrasonic energy is concentrated at a distance between 0.01-10 mm from the tip of the sonotrode of the ultrasonic device, wherein the ultrasonic energy propagates throughout the eye, wherein the effective treatment schedule is sufficient to modulate one or more biomarkers involved in promoting cell growth in the retina nerve fiber layer (RNFL), thereby increasing thickness of the RNFL.

3. The method of claim 2, wherein the one or more biomarkers are selected from mammalian target of rapamycin (mTOR), wingless-related integration site (WNT), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), brain- derived neurotrophic factor (BDNF), interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF-a), matrix metalloproteinase 3 (MMP-3), Ak strain transforming 1 (Aktl), paired box 6 (Pax6), B-cell leukemia / lymphoma 2 (Bcl-2), ciliary neurotrophic factor (CNTF), heat shock protein 70 (HSP70), and brain-specific homeobox / POU domain protein 3 (Brn3a).

4. The method of claim 2 or claim 3, wherein the one or more biomarkers are selected from brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), matrix metalloproteinase 3 (MMP-3), mammalian target of rapamycin (mTOR), tumor necrosis factor alpha (TNF-a), and combinations thereof.

5. The method of any one of claims 1-4, wherein the effective treatment schedule changes biomarker expression in the subject’s aqueous humor, trabecular meshwork, ciliary body, retina, or combinations thereof.

6. The method of any one of claims 1-5, wherein the effective treatment schedule is sufficient to increases or decrease expression level of biomarkers selected from neurotrophin 3, CNTF, HSP70, or any combination thereof.

7. The method of any one of claims 1-6, wherein the effective treatment schedule is sufficient to increase or decrease gene expression level of mTOR, WNT, NGF, GDNF, BDNF, IL-1, IL-6, IL-8, TNF-alpha, Aktl, Pax6, Bcl-2, and Brn3a in retinal ganglion cells (RGC).

8. The method of any one of claims 1-7, wherein the effective treatment schedule is sufficient to increase or decrease protein expression level of mTOR, WNT, NGF, GDNF, BDNF, IL-1, IL-6, IL-8, TNF-alpha, Aktl, Pax6, Bcl-2, and Brn3a in retinal ganglion cells (RGC).

9. The method of any one of claims 1-8, wherein the effective treatment schedule is sufficient to increase axonal growth in the RNFL or thickness of the RNFL.

10. The method of any one of claims 1-9, wherein the effective treatment schedule is sufficient to increase RNFL thickness by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 40%, 50%, 100%, 150%, 200%, 300%, 400% or more as compared to baseline.

11. The method of claim 10, wherein the RNFL thickness is measured by Heidelberg Retinal Tomography (HRT) or optical coherence tomography (OCT).

12. The method of any one of claims 1-11, wherein the effective treatment schedule is sufficient to increase the RNFL thickness in both treated and untreated eyes.

13. The method of any one of claims 1-11, wherein the ultrasound energy is applied to one eye or both eyes.

14. The method of any one of claims 1-13, wherein the effective treatment schedule is sufficient to decrease a cup to disc ratio of the eye, optionally wherein the ratio is measured by Optical coherence tomography (OCT) or Heidelberg Retinal Tomography (HRT).

15. The method of any one of claims 1-14, wherein the effective treatment schedule is sufficient to reduce intraocular pressure (IOP) in the subject’s eye.

16. The method of claim 15, wherein the effective treatment schedule is sufficient to reduce the IOP by at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% as compared to baseline.

17. The method of claim 15, wherein the effective treatment schedule is sufficient to reduce the IOP to the level of a healthy eye or lower.

18. The method of any one of claims 1-17, wherein the effective treatment schedule is sufficient to increase vision field of the eye.

19. The method of any one of claims 1-18, wherein the effective treatment schedule comprises two or more sessions of providing ultrasonic energy to the limbus of an eye.

20. The method of claim 19, wherein the effective treatment schedule comprises two sessions of providing ultrasonic energy to the limbus of an eye.

21. The method of claim 20, wherein the two sessions are scheduled 1 month, 3 months, 6 months or 12 months apart from each other.

22. The method of any one of claims 1-21 wherein the effective treatment schedule comprises three sessions of providing ultrasonic energy to the limbus of an eye.

23. The method of any one of claims 1-21, wherein the effective treatment schedule comprises providing ultrasonic energy to the limbus of an eye every 1 month, 3 months, 6 months, or 12 months or more.

24. The method of any one of claims 1-21, wherein the effective treatment schedule comprises providing ultrasonic energy to the limbus of an eye over a period of 3 months, 6 months, 9 months or 12 months.

25. The method of any one of claims 1-24, wherein the subject has glaucoma or suspected of having glaucoma.

26. The method of any one of claims 1-24, wherein the subject has not been diagnosed with glaucoma or is not suspected of having glaucoma.

27. The method of any one of claims 1-26, wherein the subject has advanced visual disease, elevated intraocular pressure, diurnal intraocular pressure (IOP), old age, decreased central corneal thickness, disc hemorrhage, genetic mutations, large beta zone of peripapillary atrophy, or optic neuropathies.

28. The method of any one of claims 1-27, wherein the subject has elevated intraocular pressure.

29. The method of any one of claims 1-28, wherein the subject has an IOP of between about 22 mmHg to about 35 mmHg before ultrasonic treatment.

30. The method of any one of claims 1-29, wherein the subject has open-angle glaucoma (OAG) or ocular hypertension.

31. The method of any one of claims 1-30 wherein the subject has damages in optic nerve.

32. The method of any one of claims 1-31, wherein the subject does not have elevated intraocular pressure.

33. The method of any one of claims 1-32, wherein the subject has normotensive glaucoma.

34. The method of any one of claims 1-33, wherein the subject has retinal nerve fiber layer (RNFL) thinner than 80 pm, thinner than 70 pm, thinner than 60 pm, thinner than 50 pm, thinner than 40 pm or thinner than an average RNFL thickness in a healthy adult.

35. The method of claim 34, wherein the subject has anemia, multiple sclerosis, age- related RNFL loss, retinitis pigmentosa, anterior ischemic optic neuropathy, high myopic retinal degeneration, or macular degeneration.

36. The method of any one of claims 1-35, wherein the subject has not received alternative glaucoma treatment before the ultrasonic treatment, optionally wherein the alternative glaucoma treatment is selected from intervention surgery and pharmaceutical treatments.

37. The method of any one of claims 1-35, wherein the subject has not received alternative glaucoma treatment before the ultrasonic treatment, wherein the alternative glaucoma treatment is selected from P-blockers, carbonic anhydrase inhibitors, prostaglandin analog, a2-adrenergic agonists, parasympathomimetic drugs, and combinations thereof.

38. The method of any one of claims 1-35, wherein the subject has received one or more alternative glaucoma treatments before the ultrasonic treatment.

39. The method of claim 38, wherein the effective treatment schedule is sufficient to reduce need for the alternative glaucoma treatment.

40. The method of any one of claims 1-39, further comprising adjusting the temperature of a portion of the eye to a temperature of between about 41 and about 45 degrees, about 40 and about 48 degrees, or about 35 and about 55 degrees centigrade.

41. The method of any one of claims 1-40, wherein the ultrasonic energy from the ultrasonic device has about 0.5-3.99 watts of power.

42. The method of any one of claims 1-40, wherein the ultrasonic energy from the ultrasonic device has about 2.0-3.99 watts of power.

43. The method of any one of claims 1-40, wherein the ultrasonic energy from the ultrasonic device has about 3.5 watts of power.

44. The method of any one of claims 1-40, wherein the ultrasonic energy from the ultrasonic device has less than 3 watts of power.

45. The method of any one of claims 1-40, wherein the ultrasonic energy from the ultrasonic device has an effective intensity of about 0.1 watts / cm2, about 0.2 watts / cm2, about 0.3 watts / cm2, about 0.4 watts / cm2, about 0.5 watts / cm2, about 0.6 watts / cm2, about 0.7 watts / cm2, about 0.8 watts / cm2, about 0.9 watts / cm2, about 1.0 watts / cm2, about 1.1 watts / cm2, about 1.2 watts / cm2, about 1.3 watts / cm2, about 1.4 watts / cm2, about 1.5 watts / cm2, about 1.6 watts / cm2, about 1.7 watts / cm2, about 1.8 watts / cm2, about 1.9 watts / cm2, about 2 watts / cm2, about 2 watts / cm2, about 2.2 watts / cm2, about 2.5 watts / cm2, about 2.8 watts / cm2, or about 3.0 watts / cm2.

46. The method of any one of claims 1-45, wherein the ultrasonic energy concentrated at the distance from the tip of the sonotrode of the ultrasonic device is less than 4 watts of power.

47. The method of claim 46, wherein the ultrasonic energy concentrated at the distance from the tip of the sonotrode of the ultrasonic device is about 3 watts of power.

48. The method of any one of claims 1-47, wherein the ultrasonic energy from the ultrasonic device has about 30-60kHz frequency.

49. The method of any one of claims 1-47, wherein the ultrasonic energy from the ultrasonic device has about 35-45kHz frequency.

50. The method of any one of claims 1-47, wherein the ultrasonic energy from the ultrasonic device has about 45kHz or 40kHz frequency.

51. The method of any one of claims 1-50, wherein the ultrasonic energy is provided for between 5 seconds and 120 seconds.

52. The method of claim 51, wherein the ultrasonic energy is applied for about 45 seconds.

53. The method of any one of claims 1-52, wherein the ultrasonic energy is applied as 10 to 15 applications wherein the 10 to 15 applications are applied while moving the tip of the sonotrode in one direction on the limbus.

54. The method of claim 53, wherein the ultrasonic energy is applied as 12 applications at 12 clock hour positions on the limbus.

55. The method of claim 53 or 54, wherein the 10 to 15 applications are applied while moving the tip of the sonotrode in the clockwise or counterclockwise direction.

56. The method of any one of claims 53-55, wherein each of the applications lasts between 5 seconds and 120 seconds.

57. The method of any one of claims 1-56, wherein the ultrasonic intensity is concentrated at a distance between 0.01-2.00 mm, 0.01-10 mm, 0.5-5 mm, or 1-3 mm from the tip of the sonotrode of the ultrasonic device.

58. The method of any one of claims 1-57, wherein the ultrasonic intensity is concentrated at a distance about 0.5mm, about 1mm, about 1.5 mm, or about 2 mm from the tip of the sonotrode of the device.

59. The method of any one of claims 1-58, wherein the ultrasound energy is provided at 45 degrees with respect to a normal vector of a surface of a limbus.

60. The method of any one of claims 1-59, wherein the ultrasound energy is divergent, low intensity and low frequency ultrasonic energy.

61. The method of any one of claims 1-60, wherein the ultrasonic device is as described in FIGs. 8A-8C.

62. The method of any one of claims 1-61, wherein the ultrasonic energy is provided toward the trabecular meshwork of the subject’s eye.

63. A device for use in a treatment method, wherein the treatment method is selected from any one of claims 1-62.

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