WO2015164419A1 - Pupillometric assessment of retinal pharmacodynamics and responses therefrom - Google Patents

Pupillometric assessment of retinal pharmacodynamics and responses therefrom Download PDF

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Publication number
WO2015164419A1
WO2015164419A1 PCT/US2015/026939 US2015026939W WO2015164419A1 WO 2015164419 A1 WO2015164419 A1 WO 2015164419A1 US 2015026939 W US2015026939 W US 2015026939W WO 2015164419 A1 WO2015164419 A1 WO 2015164419A1
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WIPO (PCT)
Prior art keywords
light
light pulse
wavelength
subject
intensity
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PCT/US2015/026939
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French (fr)
Inventor
Nathan L. Mata
Ryo Kubota
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Acucela Inc.
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Publication of WO2015164419A1 publication Critical patent/WO2015164419A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/11—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for measuring interpupillary distance or diameter of pupils
    • A61B3/112—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for measuring interpupillary distance or diameter of pupils for measuring diameter of pupils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is emixustat, or a salt thereof.
  • the visual cycle modulator is emixustat HC1.
  • the methods further comprise isolating the rod-mediated component of PLR.
  • the methods further comprise isolating the cone-mediated component of PLR.
  • the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR.
  • measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction.
  • the methods further comprise measuring the diameter of the dark-adapted pupil.
  • the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some
  • the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse is between about
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m .
  • the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2.
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 10 cd/m .
  • the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 10 lux.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2.
  • the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2.
  • the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 525 nm to about
  • intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2.
  • the wavelength of the light pulse is from about 600 nm to about 700 nm and
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux. In some embodiments,
  • the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse.
  • the images are captured with a camera.
  • the images are continuous.
  • the images are discrete.
  • the camera is an infrared camera.
  • a subject as having or being predisposed to develop an ocular disease or disorder
  • methods of diagnosing a subject comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids.
  • the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus.
  • the ocular disease or disorder is photokeratitis.
  • the methods further comprise isolating the rod-mediated component of PLR.
  • the methods further comprise isolating the cone-mediated component of PLR.
  • the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR.
  • measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction.
  • the methods further comprise measuring the diameter of the dark-adapted pupil.
  • the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some
  • the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse is between about
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m .
  • the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2.
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 10 cd/m .
  • the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 10 lux.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2.
  • the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2.
  • the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 525 nm to about
  • intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2.
  • the wavelength of the light pulse is from about 600 nm to about 700 nm and
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux. In some embodiments,
  • the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse.
  • the images are captured with a camera.
  • the images are continuous.
  • the images are discrete.
  • the camera is an infrared camera.
  • PLR pupillary light response
  • the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control.
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
  • the ocular disease or disorder is photokeratitis.
  • the visual cycle modulator is emixustat
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone -mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some embodiments, comprising exposing the individual to the light pulse for about 50 to about 100 milliseconds. In some embodiments, wherein measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil. In some
  • the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some embodiments, the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, wherein wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, wherein wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, wherein intensity of the light pulse
  • the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m . In some
  • the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of 10 cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of 10 lux. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between
  • the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2
  • wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log
  • wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m .
  • wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • wavelength of the light pulse is from about 450 nm to about
  • wavelength of the light pulse is from about 525 nm to about 575
  • intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • wavelength of the light pulse is from about 600 nm to about 700 nm and
  • the intensity of the light pulse is between 0.01 cd/m to about 999 cd/m .
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • wherein wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux.
  • the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse.
  • the images are captured with a camera.
  • the images are continuous.
  • the images are discrete.
  • the camera is an infrared camera.
  • PLR pupillary light response
  • a light source that emits a light pulse
  • a camera capable of capturing images of a pupil before, during and after exposure of the pupil to a light source
  • a software module executed by a computer processing device that analyzes pupillary light response of a subject and compares the pupillary light response to a standard or control.
  • the light source is an incandescent light source.
  • the light source is a halogen light source.
  • the light source is a LED light source.
  • the light source is a luminescent light source.
  • the light source is a fluorescent light source. In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm to about 450 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm to about 525 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 525 nm to about 575 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse
  • the intensity of the light pulse emitted by the light source is between about 0.01
  • the systems further comprise an optical filter that emits light of a wavelength from about 375 nm to about 450 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 450 nm to about 525 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 525 nm to about 575 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 600 nm to about 700 nm.
  • the optical filter is an absorptive optical filter, dichroic optical filter, or monochromatic optical filter.
  • the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 400 - 700 nm, in 10 - 25 nm increments.
  • the optical filter is an optical filter wheel which emits a light wavelength selection between 500 - 700 nm, in 10 - 25 nm increments.
  • the systems further comprise a potentiometer that adjusts the intensity of light pulse.
  • the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 1 log cd/m .
  • the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 10 cd/m . In some embodiments, the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 10 lux. In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse. In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse between about -2 log cd/m to about 2 log cd/m . In some embodiments, the optical filter adjusts the intensity of the light pulse in increments of 1 log cd/m . In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse between about 0.01 cd/m to about 999
  • the optical filter adjusts the intensity of the light pulse in increments of 10 cd/m .
  • the systems further comprise an optical filter that adjusts the intensity of the light pulse between about 0.01 lux to about 999 lux.
  • the optical filter adjusts the intensity of the light pulse in increments of 10 lux.
  • the power of the light pulse is adjustable.
  • the camera is an infrared camera. In some embodiments, the camera is capable of capturing a series of continuous images. In some embodiments, the camera is capable of capturing a series of discrete images.
  • the computer-processing device is connected to a computer network.
  • the systems further comprise electronic memory for storing the images.
  • the body that operatively covers the eye and blocks light is a pair of glasses or goggles.
  • the body that operatively covers the eye and blocks light is operatively connected to the light source.
  • the support is a chin rest.
  • the position of the support is adjustable relative to the light source and camera.
  • the position of the light source and camera are adjustable relative to the support.
  • Figure 1 exemplifies the visual cycle and key proteins which affect the pupillary light response (PLR) through genetic mutation or by pharmacologic intervention: LRAT, lecithin retinol acyltransferase; RPE65, retinal pigment epithelium-specific protein 65; 1 IcRDH, 11-cis retinol dehydrogenase; AtRDH, all-trans retinol dehydrogenase.
  • LRAT lecithin retinol acyltransferase
  • RPE65 retinal pigment epithelium-specific protein 65
  • IcRDH 11-cis retinol dehydrogenase
  • AtRDH all-trans retinol dehydrogenase.
  • Figure 2 illustrates a light-adapted pupil, a dark-adapted pupil, and a light-stimulated pupil.
  • Figure 3 exemplifies pupillary light response in a normal individual ( Figure 3 A) and an individual having an RPE65 mutation ( Figure 3B).
  • Figure 3A exemplifies pupillary light response in a normal individual ( Figure 3 A) and an individual having an RPE65 mutation ( Figure 3B).
  • Figure 4 exemplifies the effects of an RPE mutation on rod contribution to PLR (Figure 4A), cone contribution to PLR (Figure 4B), and retinal ganglion cell contribution to PLR ( Figure 4C).
  • Different light wavelength and intensity stimuli were used to isolate PLR responses for rods, cones, and retinal ganglion. There is a greater effect on the rod-component of PLR than cone-component or retinal ganglion-component.
  • Figure 5 shows the representative mouse PLR data collected using the Neuroptics A- 2000 small animal pupillometer system.
  • Figure 6 shows the effect of Compound A on the PLR in mice.
  • Figure 7 shows the effect of Compound A on pupil constriction in mice.
  • Figure 8 shows the effect of Compound A on recovery of dark-adapted pupil size in mice.
  • Figure 9 shows the effect of Compound A on rod photoreceptor activity.
  • a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone -mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is emixustat.
  • a subject as susceptible to an ocular disease or disorder, comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids.
  • the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
  • the ocular disease or disorder is photokeratitis.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control.
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
  • the ocular disease or disorder is photokeratitis.
  • the visual cycle modulator is emixustat.
  • references to “a,” “and,” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “a compound” includes a plurality of such compounds
  • reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • references to “the method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
  • VCM Video Cycle Modulation
  • the terms "subject”, “individual” and “patient” are used interchangeably. None of the terms require the supervision of a medical professional.
  • the subject is a mammal.
  • the subject is a human, non-human primate, mouse, rat, dog, cat, horse, or cow.
  • Amino refers to the -NH 2 radical.
  • Cyano refers to the -CN radical.
  • Niro refers to the -N0 2 radical.
  • Oxa refers to the -O- radical.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl).
  • an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl).
  • an alkyl comprises one to eight carbon atoms (e.g., Ci-Cg alkyl).
  • an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl).
  • an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl).
  • the alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (z ' so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • ethenyl i.e., vinyl
  • prop-l-enyl i.e., allyl
  • but-l-enyl pent-l-enyl, penta-l,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , - SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N (R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2) and -S(0) t N(R a ) 2 (where t is 1 or 2) where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocycl
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms.
  • an alkynyl comprises two to eight carbon atoms.
  • an alkynyl has two to four carbon atoms.
  • the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • Alkylene or "alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
  • alkenylene or "alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -OR a , -
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstit
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated,
  • Aryl groups include, but are not limited to, groups such as phenyl, fluorenyl, and naphthyl.
  • aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
  • each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R b is independently a direct bond or a straight or branched alkyl
  • Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, benzyl, diphenylmethyl and the like.
  • the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
  • the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
  • alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
  • the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
  • the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
  • Aralkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
  • the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
  • the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
  • Carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms.
  • a carbocyclyl comprises three to ten carbon atoms.
  • a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond.
  • Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.)
  • a fully saturated carbocyclyl radical is also referred to as "cycloalkyl.”
  • monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • An unsaturated carbocyclyl is also referred to as "cycloalkenyl.”
  • monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
  • carbocyclyl is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
  • Carbocyclylalkyl refers to a radical of the formula -R c -carbocyclyl where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo substituents.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl,
  • alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s).
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
  • heterocyclyl is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(0)-R a , -R b -N(R a ) 2 , -R b -OR a , -R b
  • N-heterocyclyl or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical.
  • An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
  • C-heterocyclyl or "C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical.
  • C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals.
  • Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
  • Heterocyclylalkyl refers to a radical of the formula -R c -heterocyclyl where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
  • Heteroaryl refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • Heteroaryl includes fused or bridged ring systems.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized.
  • heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,
  • heteroaryl is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(0)-R a , -R b -OR a , -R b -SR
  • N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
  • An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
  • a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
  • Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
  • the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
  • the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
  • Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • pharmaceutically acceptable salt of any one of the substituted heterocyclic amine derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • the visual cycle is the process by which dietary vitamin A is converted into the visual chromophore.
  • the eye has three types of photoreceptor cells: the rod cells, cone cells and non-image forming photosensitive retinal ganglion cells (also known as melanopsin-containing retinal ganglion cells). These cells convert light into electrical signals which are then interpreted by the brain.
  • Rod cells are concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 125 million rod cells in the human retina. Rod cells are almost entirely responsible for night vision.
  • Cone cells are responsible for color vision as well as eye color sensitivity. They are found in the fovea centralis. There are about six to seven million cone cells in a human eye. There are three different types of cones cells - L-cones, M-cones and S-cones. Each responds to a different wavelength of light: L-cones respond to long wavelengths (reddish color); M-cones to medium wavelengths (greenish color); and S-cones to short wavelengths (bluish color). [0058] Rod and cone cells contain rhodopsin, a pigment.
  • Rhodopsin is made up of opsins (GPCRs) that are covalently bound to the chromophore 11-cis retinal via a Schiff base. When struck by a photon, 11 -cis retinal is converted into all-trans-retinal, which uncouples from the opsin receptors. The isomerization of 11-cis retinal induces conformational changes in an opsin which starts a signal transduction cascade that results in the closure of cyclic GMP-gated cation channels, and hyperpolarization of photoreceptor cells (phototransduction).
  • GPCRs opsins
  • Regeneration of the rhodopsins requires that the chromophore be converted back to the 11-czs-configuration. Following uncoupling form an opsin, all-trans retinal is converted into all- trans retinol. All-trans retinol is then converted into 11-cis retinol in the RPE. Next, 11-cis retinol is oxidized to 11-cis retinal before traveling back to the rod outer segment where it is conjugated to an opsin to form retinylidene protein.
  • Pupillary light response is the reflex that causes constriction of the pupil in response to light. Size of the pupil is controlled by two groups of smooth muscles: the circular sphincter muscle found at the inner margin of the iris and the radially-oriented dilator muscle that runs from the peripheral border of the sphincter muscle outward toward the iris root.
  • Muscarinic receptors on the surface of the sphincter muscle mediate constriction of the pupil through parasympathetic innervation upon release of acetylcholine, while adrenergic receptors on radial fibers of the pupillary dilator muscle mediate dilation through sympathetic innervation upon norepinephrine release.
  • the PLR is mediated by the contributions from rod and cone photoreceptors in the outer retina and melanopsin-containing retinal ganglion cells located in the inner retina.
  • Rod and cone photoreceptors drive the initial rapid pupillary constriction upon exposure to continuous low-irradiance light
  • melanopsin is the primary photopigment that drives sustained pupillary constriction in response to high-irradiance light.
  • Rods initiate PLR in response to image detection in dim light of wavelengths from about 500 nm to about 600 nm.
  • Cones initiate PLR in response to image detection in bright light of wavelengths from about 600 nm to about 700 nm.
  • melanospin responds strongly to short wavelengths in the light in blue portion of the visual spectrum (-480 nm). The rate of pupillary dilation following light exposure has been shown to be largely dependent upon rod-cone signaling, with little to no involvement of melanopsin.
  • a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control.
  • a subject as susceptible to an ocular disease or disorder, comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids.
  • the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
  • the ocular disease or disorder is photokeratitis.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control.
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
  • the ocular disease or disorder is photokeratitis.
  • the pupil of the subject is isolated from light for a period of time sufficient for the pupil to become dark-adapted.
  • dark-adapted means a pupil having a diameter between about 4 and about 9 mm.
  • the pupil of the subject is isolated from light for at least about 10 minutes. In some embodiments, the pupil of the subject is isolated from light for greater than 10 minutes. In some embodiments, the pupil of the subject is isolated from light for at least 15 minutes. In some embodiments, the pupil of the subject is isolated from light for greater than 15 minutes.
  • the methods comprise exposing a pupil of an eye of the subject to a light pulse having an isolated wavelength and/or intensity. In some embodiments, the method comprises varying the duration of the light pulse, wavelength of the light pulse, the intensity of the light pulse, or any combinations thereof.
  • the individual is exposed to the light pulse for about 50 to about 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 50 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 75 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 200 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 300 milliseconds.
  • the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from 375 nm ⁇ 10 nm to 450 nm ⁇ 10 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from 450 nm ⁇ 10 nm to 525 nm ⁇ 10 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm.
  • the wavelength of the light pulse is from 525 nm ⁇ 10 nm to 575 nm ⁇ 10 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the wavelength of the light pulse is from 600 nm ⁇ 10 nm to 700 nm ⁇ 10 nm.
  • the intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the intensity of the light pulse is adjusted by increments of about 1 log cd/m .
  • the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the intensity of the light pulse is adjusted by increments of about 10 cd/m .
  • the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse is adjusted by increments of about 10 lux. [0073] In some embodiments, the wavelength of the light pulse is from about 375 nm to about
  • the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 375 ⁇ 10 nm to about 450 ⁇ 10 nm and the intensity
  • the wavelength of the light pulse is between about -2 log cd/m to about 2 log cd/m .
  • the wavelength of the light pulse is from about 375 ⁇ 10 nm to about 450 ⁇ 10 nm and the intensity of
  • the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • the wavelength of the light pulse is from about 375 ⁇ 10 nm to about 450 ⁇ 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the wavelength of the light pulse is from about 450 nm to about
  • the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 ⁇ 10 nm to about 525 ⁇ 10 nm and the intensity of
  • the light pulse is between about -2 log cd/m to about 2 log cd/m .
  • the wavelength of the light pulse is from about 450 ⁇ 10 nm to about 525 ⁇ 10 nm and the intensity of
  • the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • the wavelength of the light pulse is from about 450 ⁇ 10 nm to about 525 ⁇ 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the wavelength of the light pulse is from about 525 nm to about
  • the wavelength of the light pulse is from about 525 nm to about 575 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from 525 nm ⁇ 10 nm to 575 nm ⁇ 10 nm and the intensity of
  • the light pulse is between about -2 log cd/m to about 2 log cd/m .
  • the wavelength of the light pulse is from about 525 ⁇ 10 nm to about 575 ⁇ 10 nm and the intensity
  • the wavelength of the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • the wavelength of the light pulse is from about 525 ⁇ 10 nm to about 575 ⁇ 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the wavelength of the light pulse is from about 600 nm to about
  • the wavelength of the light pulse is from about 600 nm to about 700 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from 600 nm ⁇ 10 nm to 700 nm ⁇ 10 nm and the intensity of
  • the light pulse is between about -2 log cd/m to about 2 log cd/m .
  • the wavelength of the light pulse is from about 600 ⁇ 10 nm to about 700 ⁇ 10 nm and the intensity
  • the wavelength of the light pulse is between about 0.01 cd/m to about 999 cd/m .
  • the wavelength of the light pulse is from about 600 ⁇ 10 nm to about 700 ⁇ 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
  • the methods further comprise measuring rate of constriction of the pupil. In some embodiments, the methods further comprise measuring rate of recovery of the pupil. In some embodiments, the methods further comprise measuring minimum pupil diameter. In some embodiments, the methods further comprise measuring duration of constriction. In some embodiments, the methods further comprise measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, duration of constriction, or any combination thereof. In some embodiments, the methods further comprise measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil, for example, as a control.
  • the method further comprises capturing images of the PLR of the individual, for example with a camera, before, during and after exposure to the light pulse.
  • the images are continuous (e.g., a movie).
  • the images are discrete.
  • the camera is an infrared camera.
  • measuring the PLR of the subject comprises measuring the rate of constriction of the pupil, the rate of recovery of the pupil, the minimum pupil diameter, and the duration of constriction. In some embodiments, the method further comprises measuring the diameter of the dark-adapted pupil.
  • the methods disclosed herein enable diagnosis of an ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder, for example an ocular disease or disorder associated with dysfunction of metabolism of visual retinoids.
  • the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder associated with a mutation in RPE-specific protein 65 kDa (Rpe65); retinal-specific ATP -binding cassette transporter member 4 (ABCA4); retinol dehydrogenase 12 (RDH12); lecithin: retinol acyltransferase (LRAT); retinal G protein- coupled receptor (RGR); retinaldehyde binding protein 1 (RLBP1); retinol dehydrogenase 5 (RDH5); or any combinations thereof.
  • the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder associated with a mutation in RPE-specific protein 65 kDa (Rpe65).
  • the physician runs further diagnostic tests, to diagnose the specific disease or disorder.
  • the methods disclosed herein enable diagnosis of Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
  • the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
  • PLR pupillary light response
  • a light source that emits a light pulse
  • a camera capable of capturing images of a pupil before, during and after exposure of the pupil to a light source
  • a software module executed by a computer processing device that analyzes pupillary light response of a subject and compares the pupillary light response to a standard or control.
  • the light source emits a light pulse having an isolated wavelength. . In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm to about 450 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm ⁇ 10 nm to about 450 nm ⁇ 10 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm to about 525 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm ⁇ 10 nm to about 525 nm ⁇ 10 nm.
  • the light source emits a light pulse having a wavelength from about 525 nm to about 575 nm. In some embodiments, the light source emits a light pulse having a wavelength from 525 nm ⁇ 10 nm to 575 nm ⁇ 10 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 600 nm to about 700 nm. In some embodiments, the light source emits a light pulse having a wavelength from 600 nm ⁇ 10 nm to 700 nm ⁇ 10 nm. In some embodiments, the light source emits a light pulse having a broad range of wavelengths of light.
  • the light source is an incandescent light source, e.g., a halogen light source. In some embodiments, the light source is a LED light source. In some embodiments,
  • the light source is a luminescent light source. In some embodiments, the light source is a fluorescent light source.
  • the intensity of a light pulse emitted by the light source is between about -2 log cd/m 2 to about 2 log cd/m 2.
  • the intensity of a light pulse emitted by the light source is between between about 0.01 cd/m 2 to about 999 cd/m 2 '
  • the intensity of a light pulse emitted by the light source is between between about 0.01 lux to about 999 lux. '
  • the camera is an infrared camera. Any suitable infrared camera is contemplated for use with the PLR measurement system. In some embodiments, the camera is capable of capturing a series of continuous images (e.g., a movie) or a series of discrete images. Wavelength Adjustment
  • the PLR measurement system further comprises a means for adjusting the wavelength of the light pulse emitted by the light source.
  • the PLR measurement system further comprises an optical filter capable of adjusting the wavelength of the light pulse emitted by the light source.
  • the PLR measurement system comprises a plurality of optical filters capable of adjusting the wavelength of the light pulse emitted by the light source.
  • the optical filter adjusts wavelength of the light pulse emitted by the light source.
  • the optical filter that adjusts wavelength of the light pulse is an absorptive optical filter.
  • the optical filter that adjusts wavelength of the light pulse is a dichroic optical filter.
  • the optical filter that adjusts wavelength of the light pulse is a monochromatic optical filter. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 400 - 700 nm, in 10 - 25 nm increments. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 500 - 700 nm, in 10 - 25 nm increments. In some embodiments, the optical filter isolates light of a wavelength from about 375 nm to about 450 nm. In some embodiments, the optical filter isolates light of a wavelength from about 375 nm ⁇ 10 nm to about 450 nm ⁇ 10 nm. In some
  • the optical filter isolates light of a wavelength from about 450 nm to about 525 nm. In some embodiments, the optical filter isolates light of a wavelength from about 450 nm ⁇ 10 nm to about 525 nm ⁇ 10 nm. In some embodiments, the optical filter isolates light of a wavelength from about 525 nm to about 575 nm. In some embodiments, the optical filter isolates light of a wavelength from about 525 nm ⁇ 10 nm to about 575 nm ⁇ 10 nm. In some
  • the optical filter isolates light of a wavelength from about 600 nm to about 700 nm. In some embodiments, the optical filter isolates light of a wavelength from about 600 nm ⁇ 10 nm to about 700 nm ⁇ 10 nm.
  • the PLR measurement system further comprises a means for adjusting the intensity of the light pulse emitted by the light source. In some embodiments, the PLR measurement system comprises a means for adjusting the intensity of the light pulse
  • the intensity of the light pulse emitted by the light source is adjustable in increments of about 1 log cd/m .
  • the PLR measurement system comprises a means for adjusting the intensity of the light pulse emitted by the light source to between about 0.01 cd/m to about 999 cd/m". In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of about 10 cd/m .
  • the PLR measurement system comprises a means for adjusting the intensity of the light pulse emitted by the light source to between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of about 10 lux.
  • the power of the light source is adjustable.
  • the PLR measurement system further comprises a potentiometer for adjusting the intensity of the light pulse emitted by the light source.
  • the PLR measurement system further comprises an optical filter capable of adjusting intensity of the light pulse emitted by the source.
  • the optical filter that adjusts intensity of the light pulse is a neutral density (ND) filter.
  • the optical filter that adjusts intensity of the light pulse is ND-filter wheel.
  • the PLR measurement system further comprises body that operatively covers the eye and blocks light (an "eye cover").
  • the eye cover is a pair of glasses or goggles.
  • the eye cover is operatively connected to the light source.
  • the PLR measurement system further comprises a body that supports the head of the subject.
  • the support is a chin rest.
  • the PLR measurement system further comprise a computer- processing device, optionally connected to a computer network.
  • the PLR measurement system further comprises a software module executed by the computer-processing device to analyze pupillary light response in a subject.
  • the PLR measurement system further comprises a software module executed by the computer-processing device to compare the pupillary light response in the subject to a standard or control.
  • the PLR measurement system further comprises a support, for example a chin rest upon which the chin of the subject rests during pupillometry.
  • the position of the support is adjustable relative to the light source and camera.
  • the position of the light source and camera are adjustable relative to the support.
  • the PLR measurement systems further comprise a digital processing device, or use of the same.
  • the digital processing device includes one or more hardware central processing units (CPU) that carry out the device's functions.
  • the digital processing device further comprises an operating system configured to perform executable instructions.
  • the digital processing device is optionally connected a computer network.
  • the digital processing device is optionally connected to the Internet such that it accesses the World Wide Web.
  • the digital processing device is optionally connected to a cloud computing infrastructure.
  • the digital processing device is optionally connected to an intranet.
  • the digital processing device is optionally connected to a data storage device.
  • suitable digital processing devices include, by way of non-limiting examples, server computers, desktop computers, laptop computers, notebook computers, sub-notebook computers, netbook computers, netpad computers, set-top computers, handheld computers, Internet appliances, mobile smartphones, tablet computers, personal digital assistants, video game consoles, and vehicles.
  • server computers desktop computers, laptop computers, notebook computers, sub-notebook computers, netbook computers, netpad computers, set-top computers, handheld computers, Internet appliances, mobile smartphones, tablet computers, personal digital assistants, video game consoles, and vehicles.
  • smartphones are suitable for use in the system described herein.
  • Suitable tablet computers include those with booklet, slate, and convertible configurations, known to those of skill in the art.
  • the digital processing device includes an operating system configured to perform executable instructions.
  • the operating system is, for example, software, including programs and data, which manages the device's hardware and provides services for execution of applications.
  • suitable server operating systems include, by way of non-limiting examples, FreeBSD, OpenBSD, NetBSD ® , Linux, Apple ® Mac OS X Server ® , Oracle ® Solaris ® , Windows Server ® , and Novell ® NetWare ® .
  • suitable personal computer operating systems include, by way of non-limiting examples, Microsoft ® Windows ® , Apple ® Mac OS X ® , UNIX ® , and UNIX- like operating systems such as GNU/Linux ® .
  • the operating system is provided by cloud computing.
  • suitable mobile smart phone operating systems include, by way of non-limiting examples, Nokia ® Symbian ® OS, Apple ® iOS ® , Research In Motion ® BlackBerry OS ® , Google ® Android ® , Microsoft ® Windows Phone ® OS, Microsoft ® Windows Mobile ® OS, Linux ® , and Palm ® WebOS ® .
  • the device includes a storage and/or memory device.
  • the storage and/or memory device is one or more physical apparatuses used to store data or programs on a temporary or permanent basis.
  • the device is volatile memory and requires power to maintain stored information.
  • the device is non- volatile memory and retains stored information when the digital processing device is not powered.
  • the non-volatile memory comprises flash memory.
  • the non-volatile memory comprises dynamic random-access memory (DRAM).
  • the non-volatile memory comprises ferroelectric random access memory (FRAM).
  • the non-volatile memory comprises phase-change random access memory (PRAM).
  • the device is a storage device including, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, magnetic disk drives, magnetic tapes drives, optical disk drives, and cloud computing based storage.
  • the storage and/or memory device is a combination of devices such as those disclosed herein.
  • the digital processing device includes a display to send visual information to a user.
  • the display is a cathode ray tube (CRT).
  • the display is a liquid crystal display (LCD).
  • the display is a thin film transistor liquid crystal display (TFT-LCD).
  • the display is an organic light emitting diode (OLED) display.
  • OLED organic light emitting diode
  • on OLED display is a passive-matrix OLED (PMOLED) or active-matrix OLED (AMOLED) display.
  • the display is a plasma display.
  • the display is a video projector.
  • the display is a combination of devices such as those disclosed herein.
  • the digital processing device includes an input device to receive information from a user.
  • the input device is a keyboard.
  • the input device is a pointing device including, by way of non-limiting examples, a mouse, trackball, track pad, joystick, game controller, or stylus.
  • the input device is a touch screen or a multi-touch screen.
  • the input device is a microphone to capture voice or other sound input.
  • the input device is a video camera or other sensor to capture motion or visual input.
  • the input device is a Kinect, Leap Motion, or the like.
  • the input device is a combination of devices such as those disclosed herein.
  • Non-transitory computer readable storage medium
  • the PLR measurement systems further comprise one or more non-transitory computer readable storage media encoded with a program including instructions executable by the operating system of an optionally networked digital processing device.
  • a computer readable storage medium is a tangible component of a digital processing device.
  • a computer readable storage medium is optionally removable from a digital processing device.
  • a computer readable storage medium includes, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, solid state memory, magnetic disk drives, magnetic tape drives, optical disk drives, cloud computing systems and services, and the like.
  • the program and instructions are permanently, substantially permanently, semi-permanently, or non-transitorily encoded on the media.
  • the platforms, systems, media, and methods disclosed herein include at least one computer program, or use of the same.
  • a computer program includes a sequence of instructions, executable in the digital processing device's CPU, written to perform a specified task.
  • Computer readable instructions may be implemented as program modules, such as functions, objects, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types.
  • APIs Application Programming Interfaces
  • a computer program may be written in various versions of various languages.
  • a computer program comprises one sequence of instructions. In some embodiments, a computer program comprises a plurality of sequences of instructions. In some embodiments, a computer program is provided from one location. In other embodiments, a computer program is provided from a plurality of locations. In various embodiments, a computer program includes one or more software modules. In various embodiments, a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add-ins, or add-ons, or combinations thereof.
  • the PLR measurement systems further comprise a web application.
  • a web application in various embodiments, utilizes one or more software frameworks and one or more database systems.
  • a web application is created upon a software framework such as Microsoft ® .NET or Ruby on Rails (RoR).
  • a web application utilizes one or more database systems including, by way of non-limiting examples, relational, non-relational, object oriented, associative, and XML database systems.
  • suitable relational database systems include, by way of non-limiting examples, Microsoft ® SQL Server, mySQLTM, and Oracle ® .
  • a web application in various embodiments, is written in one or more versions of one or more languages.
  • a web application may be written in one or more markup languages, presentation definition languages, client-side scripting languages, server-side coding languages, database query languages, or combinations thereof.
  • a web application is written to some extent in a markup language such as Hypertext Markup Language (HTML), Extensible Hypertext Markup Language (XHTML), or extensible Markup Language (XML).
  • a web application is written to some extent in a presentation definition language such as Cascading Style Sheets (CSS).
  • CSS Cascading Style Sheets
  • a web application is written to some extent in a client-side scripting language such as Asynchronous Javascript and XML (AJAX), Flash ® Actionscript, Javascript, or Silverlight ® .
  • AJAX Asynchronous Javascript and XML
  • Flash ® Actionscript Javascript
  • Javascript or Silverlight ®
  • a web application is written to some extent in a server-side coding language such as Active Server Pages (ASP), ColdFusion ® , Perl, JavaTM, JavaServer Pages (JSP), Hypertext Preprocessor (PHP), PythonTM, Ruby, Tel, Smalltalk, WebDNA ® , or Groovy.
  • a web application is written to some extent in a database query language such as Structured Query Language (SQL).
  • SQL Structured Query Language
  • a web application integrates enterprise server products such as IBM ® Lotus Domino ® .
  • a web application includes a media player element.
  • a media player element utilizes one or more of many suitable multimedia technologies including, by way of non-limiting examples, Adobe ® Flash ® , HTML 5, Apple ® QuickTime ® , Microsoft ® Silverlight ® , JavaTM, and Unity ® .
  • the PLR measurement systems further comprise a mobile application provided to a mobile digital processing device.
  • the mobile application is provided to a mobile digital processing device at the time it is manufactured. In other embodiments, the mobile application is provided to a mobile digital processing device via the computer network described herein.
  • a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non- limiting examples, C, C++, C#, Objective-C, JavaTM, Javascript, Pascal, Object Pascal,
  • PythonTM PythonTM, Ruby, VB.NET, WML, and XHTML/HTML with or without CSS, or combinations thereof.
  • Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator ® , Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiFlex,
  • mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, AndroidTM SDK, BlackBerry ® SDK, BREW SDK, Palm ® OS SDK, Symbian SDK, webOS SDK, and Windows ® Mobile SDK.
  • iOS iPhone and iPad
  • AndroidTM SDK AndroidTM SDK
  • BlackBerry ® SDK BlackBerry ® SDK
  • BREW SDK Palm ® OS SDK
  • Symbian SDK Symbian SDK
  • webOS SDK webOS SDK
  • Windows ® Mobile SDK Windows ® Mobile SDK
  • the PLR measurement systems further comprise a standalone application, which is a program that is run as an independent computer process, not an add-on to an existing process, e.g., not a plug-in.
  • standalone applications are often compiled.
  • a compiler is a computer program(s) that transforms source code written in a programming language into binary object code such as assembly language or machine code. Suitable compiled programming languages include, by way of non- limiting examples, C, C++, Objective-C, COBOL, Delphi, Eiffel, JavaTM, Lisp, PythonTM, Visual Basic, and VB .NET, or combinations thereof. Compilation is often performed, at least in part, to create an executable program.
  • a computer program includes one or more executable complied applications.
  • the PLR measurement systems further comprise a web browser plug-in.
  • a plug-in is one or more software components that add specific functionality to a larger software application. Makers of software applications support plug-ins to enable third-party developers to create abilities which extend an application, to support easily adding new features, and to reduce the size of an application. When supported, plug-ins enable customizing the functionality of a software application. For example, plug-ins are commonly used in web browsers to play video, generate interactivity, scan for viruses, and display particular file types. Those of skill in the art will be familiar with several web browser plug-ins including, Adobe ® Flash ® Player, Microsoft ® Silverlight ® , and Apple ® QuickTime ® .
  • the toolbar comprises one or more web browser extensions, add-ins, or add-ons. In some embodiments, the toolbar comprises one or more explorer bars, tool bands, or desk bands.
  • plug-in frameworks are available that enable development of plug-ins in various programming languages, including, by way of non-limiting examples, C++, Delphi, JavaTM, PHP, PythonTM, and VB .NET, or combinations thereof.
  • Web browsers are software applications, designed for use with network-connected digital processing devices, for retrieving, presenting, and traversing information resources on the World Wide Web. Suitable web browsers include, by way of non-limiting examples, Microsoft ® Internet Explorer ® , Mozilla ® Firefox ® , Google ® Chrome, Apple ® Safari ® , Opera Software ® Opera ® , and KDE Konqueror. In some embodiments, the web browser is a mobile web browser.
  • Mobile web browsers are designed for use on mobile digital processing devices including, by way of non-limiting examples, handheld computers, tablet computers, netbook computers, subnotebook computers, smartphones, music players, personal digital assistants (PDAs), and handheld video game systems.
  • Suitable mobile web browsers include, by way of non-limiting examples, Google ® Android ® browser, RIM BlackBerry ® Browser, Apple ® Safari ® , Palm ® Blazer, Palm ® WebOS ® Browser, Mozilla ® Firefox ® for mobile, Microsoft ® Internet Explorer ® Mobile, Amazon ® Kindle ® Basic Web, Nokia ® Browser, Opera Software ® Opera ® Mobile, and Sony ® PSPTM browser.
  • the PLR measurement systems further comprise software, server, and/or database modules, or use of the same.
  • software modules are created by techniques known to those of skill in the art using machines, software, and languages known to the art.
  • the software modules disclosed herein are
  • a software module comprises a file, a section of code, a programming object, a programming structure, or combinations thereof.
  • a software module comprises a plurality of files, a plurality of sections of code, a plurality of programming objects, a plurality of programming structures, or combinations thereof.
  • the one or more software modules comprise, by way of non-limiting examples, a web application, a mobile application, and a standalone application.
  • software modules are in one computer program or application.
  • software modules are in more than one computer program or application.
  • software modules are hosted on one machine.
  • software modules are hosted on more than one machine.
  • software modules are hosted on cloud computing platforms.
  • software modules are hosted on one or more machines in one location. In other embodiments, software modules are hosted on one or more machines in more than one location. Databases
  • the PLR measurement systems further comprise one or more databases, or use of the same.
  • suitable databases include, by way of non-limiting examples, relational databases, non-relational databases, object oriented databases, object databases, entity-relationship model databases, associative databases, and XML databases.
  • a database is internet-based.
  • a database is web- based.
  • a database is cloud computing-based.
  • a database is based on one or more local computer storage devices.
  • a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod- mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR.
  • the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control.
  • PLR pupillary light response
  • the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
  • the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control.
  • the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
  • the ocular disease or disorder is photokeratitis.
  • the visual cycle modulator is a modulator of retinol binding protein transthyretin, rhodopsin, all-trans retinol dehydrogenase, lecithin retinol acyltransferase, RPE-specific 65 kDa protein, 11-cis-retinol dehydrogenase, or a combination thereof.
  • the visual cycle modulator is an inhibitor of a member of the visual cycle.
  • the visual cycle modulator is in an inhibitor of RPE-specific 65 kDa protein (RPE65).
  • the inhibitor of RPE65 is emixustat.
  • the visual cycle modulator is a compound of Formula (A), or tautomer, stereoisomer, geometric isomer, N-oxide or a pharmaceutically acceptable salt thereof:
  • Y is selected from:
  • R is hydrogen and R is hydroxyl; or R and R form an oxo; R 7 is hydrogen;
  • R is hydrogen or CH 3 ;
  • each R 9 is independently hydrogen, or a substituted or unsubstituted C 1 -C4 alkyl; each 33
  • R is independently selected from halogen, or a substituted or unsubstituted C 1 -C4 alkyl, and n is 0, 1, 2, 3, or 4.
  • n 0, 1, or 2.
  • X is -C(R 9 ) 2 -0-. In some embodiments, X is -C(R 9 ) 2 -C(R 9 ) 2 -. In some embodiments, X is -C(R 9 ) 2 -S-. In some embodiments, X is -C(R 9 ) 2 -S(0) 2 -. In some embodiments, X is -C(R 9 ) 2 -NR 9 -.
  • Y is substituted or unsubstituted carbocyclyl, or substituted or unsubstituted C 3 -Cio alkyl. In some embodiments, Y is substituted or
  • the substituted or unsubstituted carbocyclyl is a substituted or unsubstituted 4-, 5-, 6-, or 7-membered ring. In some embodiments, the substituted or unsubstituted carbocyclyl is a 6-membered ring. In some embodiments, the substituted or unsubstituted 6-membered ring is a substituted or unsubstituted cyclohexyl. In some embodiments, the substituted or unsubstituted 6-membered ring is a substituted or unsubstituted cyclohexyl and X is -C(R 9 ) 2 -0-.
  • Y is substituted or unsubstituted C 3 -Cio alkyl.
  • the substituted or unsubstituted C 3 -Cio alkyl is a substituted or unsubstituted C 3 - C 6 alkyl.
  • the substituted C 3 -C 6 alkyl is substituted with an Ci-C 2 alkoxy group.
  • the substituted C 3 -C 6 alkyl is -CH 2 CH 2 CH 2 OCH 3 . 1 2
  • R is hydrogen and R is hydroxyl. In some embodiments,
  • R and R" form an oxo.
  • R is hydrogen. In some embodiments, R is
  • R is hydrogen, R is hydroxyl and X is -C(R ) 2 -0-.
  • the visual cycle modulator is a compound, or tautomer, stereoisomer, geometric isomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator is a compound, or tautomer, stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator a compound, or tautomer, stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator is a compound, or tautomer, tereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, stereoisomer, -oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
  • the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure: EXAMPLES
  • Study Design Phase 1, single-site, controlled and randomized, open label study
  • Randomization 40 subjects randomized 1 : 1 : 1 : 1 to placebo, 10 mg, 20 mg, and 40 mg 13 -cis retinoic acid
  • the child is fitted with diagnostic device which blocks light. After 10 minutes of complete dark adaptation a 100 millisecond light pulse is flashed. An infrared camera captures the PLR of the child. A physician compares the child's PLR to a control. The child's PLR matches the control.
  • the child is fitted with diagnostic device which blocks light. After 10 minutes of complete dark adaptation a 100 millisecond light pulse is flashed. An infrared camera captures the PLR of the child. A physician compares the child's PLR to a control. The child's PLR is attenuated compared to the control. The child is referred to a pediatric retinal specialist for further evaluation.
  • An individual diagnosed with geographic atrophy associated with dry AMD is administered a daily dosage of 5 mg of emixustat for 1 month. After 1 month, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. A physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before
  • emixustat administration of emixustat.
  • the physician increases the daily dosage of emixustat to 10 mg.
  • An individual diagnosed with geographic atrophy associated with dry AMD is administered a daily dosage of 5 mg of emixustat for 1 month. After 1 month, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. A physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before
  • emixustat administration of emixustat.
  • the physician increases the daily dosage of emixustat to 10 mg.
  • mice were between 6 and 12 weeks old and approximately 25 g each. Animals were dark adapted for a minimum of 12 hours; all subsequent procedures were performed under dim red light. Mice were dosed by oral gavage with Compound A (a representative visual cycle modulator), or vehicle (water), as indicated under dim red light.
  • Compound A a representative visual cycle modulator
  • vehicle water
  • PLR pupillary light response
  • mice were anesthetized intraperitoneally with a mixture of ketamine (60mg/kg) and xylazine (6mg/kg). Body temperature was maintained on a heating pad. Eyes were kept moist during pupillometry reading by applying Celluvisc eye drops. Pupillometry readings were recorded using a
  • Neuroptics A-2000 small animal pupillometer system. This system is equipped with an infrared camera which collects real-time video of changes in pupil size. The PLR was recorded for 5 seconds before and after a 100 ms green light pulse (528 nm). As the software is programed to report lux values, the light intensities for the following experiment is reported in lux units rather than in cd/m . PLR measurements were taken at 8 increasing light intensities: 80 lux, 125 lux, 200 lux, 250 lux, 325 lux, 400 lux, 500 lux, and 630 lux. A 3 minute recovery was allowed between pulses.
  • Figure 5 shows the representative mouse PLR data collected using the Neuroptics
  • A-2000 small animal pupillometer system The images show video captures of a pupil from an untreated mouse eye at three phases of the PLR: 1) Dark-adapted phase; 2) Constriction phase; and 3) Recovery phase.
  • the graphical tracing below the images is a plot of the pupil size (diameter in mm) as a function of time. Pupil size measurements are recorded every 30 milliseconds during the entire time course (0 - 5 seconds).
  • Figure 6 shows the effect of Compound A on the PLR in mice. Dark-adapted mice were treated with drug vehicle (Control; Figure 6A) or Compound A (3 mg/kg or 10 mg/kg; Figures 6B and 6C respectively) 6 hours prior to collecting PLR measurements.
  • mice treated with drug vehicle show a light dependent pupil constriction and delay in recovery of the dark-adapted pupil size. Pupil constriction in mice treated with Compound A is less pronounced and shows no dependence on light at higher intensities.
  • Figure 7 shows the effect of Compound A on pupil constriction in mice.
  • Pre bleach recordings in response to 0.01 cd*s/m2 were assessed after a 5 minute recovery from red light exposure. Mice were photobleached (400 cd/m2, 30 sec) and scotopic ERG b wave responses (amplitudes in ⁇ ) to 0.01 cd*s/m2 stimuli were recorded every 2 minutes for 50 minutes.
  • Figure 9 shows the effect of Compound A on rod photoreceptor activity.
  • Rod photoreceptor-derived b-wave amplitudes are plotted as a function of recovery time after photobleach.
  • B-wave response amplitudes ( ⁇ ), at each corresponding time point of recovery, are shown as mean values ⁇ SEM for each of the treatment groups. Treatment with Compound A produced a dose-dependent suppression of b-wave response amplitudes.

Abstract

Disclosed herein are methods of predicting a subject's response to a visual cycle modulator, methods of diagnosing a subject susceptible to an ocular disease or disorder, methods of guiding dose selection of a visual cycle modulator, methods of treating an ocular disease, and systems for measuring pupillary light response (PLR).

Description

PUPILLOMETRIC ASSESSMENT OF RETINAL PHARMACODYNAMICS AND
RESPONSES THEREFROM
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Serial No.
61/982,788, filed April 22, 2014, which is hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
[0002] Disclosed herein, in certain embodiments, are methods of adjusting the dose of a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is emixustat, or a salt thereof.
Figure imgf000003_0001
emixustat,
In some embodiments, the visual cycle modulator is emixustat HC1. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some embodiments, comprising exposing the individual to the light pulse for about 50 to about 100 milliseconds. In some embodiments, wherein measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil. In some embodiments, the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some
embodiments, the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse is between about
2 2
-2 log cd/m to about 2 log cd/m . In some embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some
embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 10 cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 10 lux. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log
2 2
cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 525 nm to about
575 nm and intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and
2 2
intensity of the light pulse is between 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux. In some
embodiments, the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse. In some embodiments, the images are captured with a camera. In some embodiments, the images are continuous. In some embodiments, the images are discrete. In some embodiments, the camera is an infrared camera.
[0003] Disclosed herein, in certain embodiments, are methods of diagnosing a subject as having or being predisposed to develop an ocular disease or disorder, comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, greater suppression of pupillary light response as compared to the standard or control is indicative of an increased likelihood of having or developing an ocular disease or disorder. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some
embodiments, the ocular disease or disorder is photokeratitis. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some embodiments, comprising exposing the individual to the light pulse for about 50 to about 100 milliseconds. In some embodiments, wherein measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil. In some embodiments, the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some
embodiments, the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse is between about
2 2
-2 log cd/m to about 2 log cd/m . In some embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some
embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 10 cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 10 lux. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log
2 2
cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 525 nm to about
575 nm and intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and
2 2
intensity of the light pulse is between 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux. In some
embodiments, the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse. In some embodiments, the images are captured with a camera. In some embodiments, the images are continuous. In some embodiments, the images are discrete. In some embodiments, the camera is an infrared camera.
[0004] Disclosed herein, in certain embodiments, are methods of treating an ocular disease or disorder in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) changing or maintaining the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (ii) derived from the subject prior to administration of the visual cycle modulator; wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis. In some embodiments, the visual cycle modulator is emixustat,
Figure imgf000007_0001
emixustat, or a salt thereof. In some embodiments, the visual cycle modulator is emixustat HC1. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone -mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some embodiments, comprising exposing the individual to the light pulse for about 50 to about 100 milliseconds. In some embodiments, wherein measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil. In some
embodiments, the methods further comprise isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted. In some embodiments, the methods further comprise isolating the pupil of the subject from light for at least 10 minutes. In some embodiments, the methods further comprise isolating the pupil of the subject from light for greater than 10 minutes. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, wherein wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, wherein wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, wherein intensity of the light pulse
2 2
is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the methods further comprise adjusting the intensity of the light pulse by increments of about 1 log cd/m . In some
2 2 embodiments, the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of 10 cd/m . In some embodiments, the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of 10 lux. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between
2 2
about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about -2
2 2
log cd/m to about 2 log cd/m . In some embodiments, wherein wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log
2 2
cd/m to about 2 log cd/m . In some embodiments, wherein wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 nm to about
2 2
525 nm and the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, wherein wavelength of the light pulse is from about 525 nm to about 575
2 2
nm and intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, wherein wavelength of the light pulse is from about 600 nm to about 700 nm and
2 2
intensity of the light pulse is between 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, wherein wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, wherein wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between 0.01 lux to about 999 lux. In some embodiments, the methods further comprise capturing images of the PLR before, during and after exposure to the light pulse. In some embodiments, the images are captured with a camera. In some embodiments, the images are continuous. In some embodiments, the images are discrete. In some embodiments, the camera is an infrared camera.
[0005] Disclosed herein, in certain embodiments, are systems for measuring pupillary light response (PLR), comprising (a) a light source that emits a light pulse, (b) a camera capable of capturing images of a pupil before, during and after exposure of the pupil to a light source; and (c) a software module executed by a computer processing device that analyzes pupillary light response of a subject and compares the pupillary light response to a standard or control. In some embodiments, the light source is an incandescent light source. In some embodiments, the light source is a halogen light source. In some embodiments, the light source is a LED light source. In some embodiments, the light source is a luminescent light source. In some embodiments, the light source is a fluorescent light source. In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm to about 450 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm to about 525 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 525 nm to about 575 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 600 nm to about 700 nm. In some embodiments, the intensity of the light pulse
2 2
emitted by the light source is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the intensity of the light pulse emitted by the light source is between about 0.01
2 2
cd/m to about 999 cd/m . In some embodiments, the intensity of the light pulse emitted by the light source is between about 0.01 lux to about 999 lux. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 375 nm to about 450 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 450 nm to about 525 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 525 nm to about 575 nm. In some embodiments, the systems further comprise an optical filter that emits light of a wavelength from about 600 nm to about 700 nm. In some embodiments, the optical filter is an absorptive optical filter, dichroic optical filter, or monochromatic optical filter. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 400 - 700 nm, in 10 - 25 nm increments. In some embodiments, the optical filter is an optical filter wheel which emits a light wavelength selection between 500 - 700 nm, in 10 - 25 nm increments. In some embodiments, the systems further comprise a potentiometer that adjusts the intensity of light pulse. In some embodiments, the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 1 log cd/m . In some embodiments, the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 10 cd/m . In some embodiments, the systems further comprise a potentiometer that adjusts the intensity of light pulse in increments of 10 lux. In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse. In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse between about -2 log cd/m to about 2 log cd/m . In some embodiments, the optical filter adjusts the intensity of the light pulse in increments of 1 log cd/m . In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse between about 0.01 cd/m to about 999
2
cd/m . In some embodiments, the optical filter adjusts the intensity of the light pulse in increments of 10 cd/m . In some embodiments, the systems further comprise an optical filter that adjusts the intensity of the light pulse between about 0.01 lux to about 999 lux. In some embodiments, the optical filter adjusts the intensity of the light pulse in increments of 10 lux. In some embodiments, the power of the light pulse is adjustable. In some embodiments, the camera is an infrared camera. In some embodiments, the camera is capable of capturing a series of continuous images. In some embodiments, the camera is capable of capturing a series of discrete images. In some embodiments, the computer-processing device is connected to a computer network. In some embodiments, the systems further comprise electronic memory for storing the images. In some embodiments, further comprising a body that operatively covers the eye and blocks light. In some embodiments, the body that operatively covers the eye and blocks light is a pair of glasses or goggles. In some embodiments, the body that operatively covers the eye and blocks light is operatively connected to the light source. In some embodiments, further comprising body that supports the head of the subject. In some embodiments, the support is a chin rest. In some embodiments, the position of the support is adjustable relative to the light source and camera. In some embodiments, the position of the light source and camera are adjustable relative to the support.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative
embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
[0007] Figure 1 exemplifies the visual cycle and key proteins which affect the pupillary light response (PLR) through genetic mutation or by pharmacologic intervention: LRAT, lecithin retinol acyltransferase; RPE65, retinal pigment epithelium-specific protein 65; 1 IcRDH, 11-cis retinol dehydrogenase; AtRDH, all-trans retinol dehydrogenase.
[0008] Figure 2 illustrates a light-adapted pupil, a dark-adapted pupil, and a light-stimulated pupil.
[0009] Figure 3 exemplifies pupillary light response in a normal individual (Figure 3 A) and an individual having an RPE65 mutation (Figure 3B). During dark adaptation, pupil sizes in both individuals are comparable. Light stimulus (at t=0) produces a pupil constriction in the normal subject (about 55% of the dark value). Light stimulus (at t=0) produces a less robust pupil constriction in the affected subject (about 76% of the dark value).
[0010] Figure 4 exemplifies the effects of an RPE mutation on rod contribution to PLR (Figure 4A), cone contribution to PLR (Figure 4B), and retinal ganglion cell contribution to PLR (Figure 4C). Different light wavelength and intensity stimuli were used to isolate PLR responses for rods, cones, and retinal ganglion. There is a greater effect on the rod-component of PLR than cone-component or retinal ganglion-component.
[0011] Figure 5 shows the representative mouse PLR data collected using the Neuroptics A- 2000 small animal pupillometer system.
[0012] Figure 6 shows the effect of Compound A on the PLR in mice.
[0013] Figure 7 shows the effect of Compound A on pupil constriction in mice.
[0014] Figure 8 shows the effect of Compound A on recovery of dark-adapted pupil size in mice. [0015] Figure 9 shows the effect of Compound A on rod photoreceptor activity.
DETAILED DESCRIPTION OF THE INVENTION
[0016] Disclosed herein, in certain embodiments, are methods of adjusting the dose of a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone -mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is emixustat.
[0017] Disclosed herein, in certain embodiments, are methods diagnosing a subject as susceptible to an ocular disease or disorder, comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, greater suppression of pupillary light response as compared to the standard or control is indicative of an increased likelihood of having or developing an ocular disease or disorder. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis.
[0018] Disclosed herein, in certain embodiments, are methods of treating an ocular disease or disorder in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) changing or maintaining the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard, wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis. In some embodiments, the visual cycle modulator is emixustat.
Certain Terminology
[0019] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0020] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. Also, for example, references to "the method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub -combinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or
"including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.
[0021] As used herein, "Visual Cycle Modulation" (VCM) refers to the process of slowing the production of chromophore in the visual cycle by inhibition of a key enzyme or protein.
[0022] The terms "subject", "individual" and "patient" are used interchangeably. None of the terms require the supervision of a medical professional. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human, non-human primate, mouse, rat, dog, cat, horse, or cow.
[0023] Amino" refers to the -NH2 radical.
[0024] "Cyano" refers to the -CN radical.
[0025] "Nitro" refers to the -N02 radical.
[0026] "Oxa" refers to the -O- radical.
[0027] "Oxo" refers to the =0 radical.
[0028] "Thioxo" refers to the =S radical. [0029] "Imino" refers to the =N-H radical.
[0030] "Hydrazino" refers to the =N-NH2 radical.
[0031] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cg alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). The alkyl is attached to the rest of the molecule by a single bond, for example, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (z'so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -
SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, -N (Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0032] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, - SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, -N (Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0033] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -
SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, -N (Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0034] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -ORa, -
SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, -N (Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
[0035] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, for example, ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a double bond or a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, -ORa, -
SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, -N (Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2) and -S(0)tN(Ra)2 (where t is 1 or 2) where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0036] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic
hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated,
1. e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Huckel theory. Aryl groups include, but are not limited to, groups such as phenyl, fluorenyl, and naphthyl. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)
2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0037] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, benzyl, diphenylmethyl and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0038] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
[0039] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
[0040] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated, (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(0)-Ra, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C (0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0041] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rc is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.
[0042] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents. [0043] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl,
2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
[0044] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(0)-Ra, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C (0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0045] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.
[0046] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A
C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.
[0047] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rc is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.
[0048] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,
benzo[d]thiazolyl, benzothiadiazolyl, benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,
1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5.6.7.8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6.7.8.9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(0)-Ra, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)ORa, -Rb-C (0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.
[0049] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0050] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0051] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
[0052] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
[0053] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A
pharmaceutically acceptable salt of any one of the substituted heterocyclic amine derivative compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
The Visual Cycle
[0054] The visual cycle is the process by which dietary vitamin A is converted into the visual chromophore.
[0055] The eye has three types of photoreceptor cells: the rod cells, cone cells and non-image forming photosensitive retinal ganglion cells (also known as melanopsin-containing retinal ganglion cells). These cells convert light into electrical signals which are then interpreted by the brain.
[0056] Rod cells are concentrated at the outer edges of the retina and are used in peripheral vision. On average, there are approximately 125 million rod cells in the human retina. Rod cells are almost entirely responsible for night vision.
[0057] Cone cells are responsible for color vision as well as eye color sensitivity. They are found in the fovea centralis. There are about six to seven million cone cells in a human eye. There are three different types of cones cells - L-cones, M-cones and S-cones. Each responds to a different wavelength of light: L-cones respond to long wavelengths (reddish color); M-cones to medium wavelengths (greenish color); and S-cones to short wavelengths (bluish color). [0058] Rod and cone cells contain rhodopsin, a pigment. Rhodopsin is made up of opsins (GPCRs) that are covalently bound to the chromophore 11-cis retinal via a Schiff base. When struck by a photon, 11 -cis retinal is converted into all-trans-retinal, which uncouples from the opsin receptors. The isomerization of 11-cis retinal induces conformational changes in an opsin which starts a signal transduction cascade that results in the closure of cyclic GMP-gated cation channels, and hyperpolarization of photoreceptor cells (phototransduction).
[0059] Regeneration of the rhodopsins requires that the chromophore be converted back to the 11-czs-configuration. Following uncoupling form an opsin, all-trans retinal is converted into all- trans retinol. All-trans retinol is then converted into 11-cis retinol in the RPE. Next, 11-cis retinol is oxidized to 11-cis retinal before traveling back to the rod outer segment where it is conjugated to an opsin to form retinylidene protein.
Pupillary Light Response
[0060] Pupillary light response (PLR) is the reflex that causes constriction of the pupil in response to light. Size of the pupil is controlled by two groups of smooth muscles: the circular sphincter muscle found at the inner margin of the iris and the radially-oriented dilator muscle that runs from the peripheral border of the sphincter muscle outward toward the iris root.
Muscarinic receptors on the surface of the sphincter muscle mediate constriction of the pupil through parasympathetic innervation upon release of acetylcholine, while adrenergic receptors on radial fibers of the pupillary dilator muscle mediate dilation through sympathetic innervation upon norepinephrine release.
[0061] Under normal physiological/anatomical conditions, the PLR is mediated by the contributions from rod and cone photoreceptors in the outer retina and melanopsin-containing retinal ganglion cells located in the inner retina. Rod and cone photoreceptors drive the initial rapid pupillary constriction upon exposure to continuous low-irradiance light, whereas melanopsin is the primary photopigment that drives sustained pupillary constriction in response to high-irradiance light.
[0062] Rods initiate PLR in response to image detection in dim light of wavelengths from about 500 nm to about 600 nm. Cones initiate PLR in response to image detection in bright light of wavelengths from about 600 nm to about 700 nm. On the other hand, melanospin responds strongly to short wavelengths in the light in blue portion of the visual spectrum (-480 nm). The rate of pupillary dilation following light exposure has been shown to be largely dependent upon rod-cone signaling, with little to no involvement of melanopsin.
[0063] Disclosed herein, in certain embodiments, are methods of adjusting the dose of a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control.
[0064] Disclosed herein, in certain embodiments, are methods diagnosing a subject as susceptible to an ocular disease or disorder, comprising: (a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and (b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; or (ii) derived from an individual or population of individuals who have or have had an ocular disease; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, greater suppression of pupillary light response as compared to the standard or control is indicative of an increased likelihood of having or developing an ocular disease or disorder. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis.
[0065] Disclosed herein, in certain embodiments, are methods of treating an ocular disease or disorder in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) changing or maintaining the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard, wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis.
[0066] In some embodiments, the pupil of the subject is isolated from light for a period of time sufficient for the pupil to become dark-adapted. As used herein, "dark-adapted" means a pupil having a diameter between about 4 and about 9 mm. In some embodiments, the pupil of the subject is isolated from light for at least about 10 minutes. In some embodiments, the pupil of the subject is isolated from light for greater than 10 minutes. In some embodiments, the pupil of the subject is isolated from light for at least 15 minutes. In some embodiments, the pupil of the subject is isolated from light for greater than 15 minutes.
[0067] In some embodiments, the methods comprise exposing a pupil of an eye of the subject to a light pulse having an isolated wavelength and/or intensity. In some embodiments, the method comprises varying the duration of the light pulse, wavelength of the light pulse, the intensity of the light pulse, or any combinations thereof.
[0068] In some embodiments, the individual is exposed to the light pulse for about 50 to about 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 50 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 75 milliseconds. In some embodiments, the individual is exposed to the light pulse for greater than 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 100 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 200 milliseconds. In some embodiments, the individual is exposed to the light pulse for less than 300 milliseconds.
[0069] In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm. In some embodiments, the wavelength of the light pulse is from 375 nm ± 10 nm to 450 nm ± 10 nm. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm. In some embodiments, the wavelength of the light pulse is from 450 nm ± 10 nm to 525 nm ± 10 nm. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm. In some embodiments, the wavelength of the light pulse is from 525 nm ± 10 nm to 575 nm ± 10 nm. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm. In some embodiments, the wavelength of the light pulse is from 600 nm ± 10 nm to 700 nm ± 10 nm.
[0070] In some embodiments, the intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the intensity of the light pulse is adjusted by increments of about 1 log cd/m .
[0071] In some embodiments, the intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the intensity of the light pulse is adjusted by increments of about 10 cd/m .
[0072] In some embodiments, the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse is adjusted by increments of about 10 lux. [0073] In some embodiments, the wavelength of the light pulse is from about 375 nm to about
450 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 375 nm to about 450 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 375 ± 10 nm to about 450 ± 10 nm and the intensity
2 2
of the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 375± 10 nm to about 450± 10 nm and the intensity of
2 2
the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 375 ± 10 nm to about 450 ± 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
[0074] In some embodiments, the wavelength of the light pulse is from about 450 nm to about
525 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 450 nm to about 525 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from about 450± 10 nm to about 525± 10 nm and the intensity of
2 2
the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 450± 10 nm to about 525± 10 nm and the intensity of
2 2
the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 450 ± 10 nm to about 525 ± 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
[0075] In some embodiments, the wavelength of the light pulse is from about 525 nm to about
575 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 525 nm to about 575 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from 525 nm ± 10 nm to 575 nm ± 10 nm and the intensity of
2 2
the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 525 ± 10 nm to about 575 ± 10 nm and the intensity
2 2
of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 525 ± 10 nm to about 575 ± 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
[0076] In some embodiments, the wavelength of the light pulse is from about 600 nm to about
700 nm and the intensity of the light pulse is between about -2 log cd/m 2 to about 2 log cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and the intensity of the light pulse is between about 0.01 cd/m 2 to about 999 cd/m 2. In some embodiments, the wavelength of the light pulse is from about 600 nm to about 700 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux. In some embodiments, the wavelength of the light pulse is from 600 nm ± 10 nm to 700 nm ± 10 nm and the intensity of
2 2
the light pulse is between about -2 log cd/m to about 2 log cd/m . In some embodiments, the wavelength of the light pulse is from about 600 ± 10 nm to about 700 ± 10 nm and the intensity
2 2
of the light pulse is between about 0.01 cd/m to about 999 cd/m . In some embodiments, the wavelength of the light pulse is from about 600 ± 10 nm to about 700 ± 10 nm and the intensity of the light pulse is between about 0.01 lux to about 999 lux.
[0077] In some embodiments, the methods further comprise measuring rate of constriction of the pupil. In some embodiments, the methods further comprise measuring rate of recovery of the pupil. In some embodiments, the methods further comprise measuring minimum pupil diameter. In some embodiments, the methods further comprise measuring duration of constriction. In some embodiments, the methods further comprise measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, duration of constriction, or any combination thereof. In some embodiments, the methods further comprise measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter and duration of constriction. In some embodiments, the methods further comprise measuring the diameter of the dark-adapted pupil, for example, as a control.
[0078] In some embodiments, the method further comprises capturing images of the PLR of the individual, for example with a camera, before, during and after exposure to the light pulse. In some embodiments, the images are continuous (e.g., a movie). In some embodiments, the images are discrete. In some embodiments, the camera is an infrared camera.
[0079] In some embodiments, measuring the PLR of the subject comprises measuring the rate of constriction of the pupil, the rate of recovery of the pupil, the minimum pupil diameter, and the duration of constriction. In some embodiments, the method further comprises measuring the diameter of the dark-adapted pupil.
[0080] In some embodiments, the methods disclosed herein enable diagnosis of an ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder, for example an ocular disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder associated with a mutation in RPE-specific protein 65 kDa (Rpe65); retinal-specific ATP -binding cassette transporter member 4 (ABCA4); retinol dehydrogenase 12 (RDH12); lecithin: retinol acyltransferase (LRAT); retinal G protein- coupled receptor (RGR); retinaldehyde binding protein 1 (RLBP1); retinol dehydrogenase 5 (RDH5); or any combinations thereof. In some embodiments, the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop an ocular disease or disorder associated with a mutation in RPE-specific protein 65 kDa (Rpe65).
[0081] In some embodiments, upon a positive indication that the individual is afflicted with or predisposed to develop an ocular disease or disorder, for example an ocular disease or disorder associated with dysfunction of metabolism of visual retinoids, the physician runs further diagnostic tests, to diagnose the specific disease or disorder.
[0082] In some embodiments, the methods disclosed herein enable diagnosis of Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the methods disclosed herein indicate whether an individual is afflicted with or predisposed to develop Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens;
Bothnia dystrophy; and fundus albipunctatus.
PLR Measurement System
[0083] Disclosed herein, in certain embodiments, are systems for measuring pupillary light response (PLR), comprising (a) a light source that emits a light pulse, (b) a camera capable of capturing images of a pupil before, during and after exposure of the pupil to a light source; and (c) a software module executed by a computer processing device that analyzes pupillary light response of a subject and compares the pupillary light response to a standard or control.
Light Source
[0084] In some embodiments, the light source emits a light pulse having an isolated wavelength. . In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm to about 450 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 375 nm ± 10 nm to about 450 nm ± 10 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm to about 525 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 450 nm ± 10 nm to about 525 nm ± 10 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 525 nm to about 575 nm. In some embodiments, the light source emits a light pulse having a wavelength from 525 nm ± 10 nm to 575 nm ± 10 nm. In some embodiments, the light source emits a light pulse having a wavelength from about 600 nm to about 700 nm. In some embodiments, the light source emits a light pulse having a wavelength from 600 nm ± 10 nm to 700 nm ± 10 nm. In some embodiments, the light source emits a light pulse having a broad range of wavelengths of light.
[0085] In some embodiments, the light source is an incandescent light source, e.g., a halogen light source. In some embodiments, the light source is a LED light source. In some
embodiments, the light source is a luminescent light source. In some embodiments, the light source is a fluorescent light source.
[0086] In some embodiments, the intensity of a light pulse emitted by the light source is between about -2 log cd/m 2 to about 2 log cd/m 2.
[0087] In some embodiments, the intensity of a light pulse emitted by the light source is between between about 0.01 cd/m 2 to about 999 cd/m 2 '
[0088] In some embodiments, the intensity of a light pulse emitted by the light source is between between about 0.01 lux to about 999 lux.'
Camera
[0089] In some embodiments, the camera is an infrared camera. Any suitable infrared camera is contemplated for use with the PLR measurement system. In some embodiments, the camera is capable of capturing a series of continuous images (e.g., a movie) or a series of discrete images. Wavelength Adjustment
[0090] In some embodiments, the PLR measurement system further comprises a means for adjusting the wavelength of the light pulse emitted by the light source. In some embodiments, the PLR measurement system further comprises an optical filter capable of adjusting the wavelength of the light pulse emitted by the light source. In some embodiments, the PLR measurement system comprises a plurality of optical filters capable of adjusting the wavelength of the light pulse emitted by the light source. In some embodiments, the optical filter adjusts wavelength of the light pulse emitted by the light source. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an absorptive optical filter. In some embodiments, the optical filter that adjusts wavelength of the light pulse is a dichroic optical filter. In some embodiments, the optical filter that adjusts wavelength of the light pulse is a monochromatic optical filter. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 400 - 700 nm, in 10 - 25 nm increments. In some embodiments, the optical filter that adjusts wavelength of the light pulse is an optical filter wheel which permits a light wavelength selection between 500 - 700 nm, in 10 - 25 nm increments. In some embodiments, the optical filter isolates light of a wavelength from about 375 nm to about 450 nm. In some embodiments, the optical filter isolates light of a wavelength from about 375 nm ± 10 nm to about 450 nm ± 10 nm. In some
embodiments, the optical filter isolates light of a wavelength from about 450 nm to about 525 nm. In some embodiments, the optical filter isolates light of a wavelength from about 450 nm ± 10 nm to about 525 nm ± 10 nm. In some embodiments, the optical filter isolates light of a wavelength from about 525 nm to about 575 nm. In some embodiments, the optical filter isolates light of a wavelength from about 525 nm ± 10 nm to about 575 nm ± 10 nm. In some
embodiments, the optical filter isolates light of a wavelength from about 600 nm to about 700 nm. In some embodiments, the optical filter isolates light of a wavelength from about 600 nm ± 10 nm to about 700 nm ± 10 nm.
Intensity Adjustment
[0091] In some embodiments, the PLR measurement system further comprises a means for adjusting the intensity of the light pulse emitted by the light source. In some embodiments, the PLR measurement system comprises a means for adjusting the intensity of the light pulse
2 2
emitted by the light source to between about -2 log cd/m to about 2 log cd/m . In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of about 1 log cd/m .
[0092] In some embodiments, the PLR measurement system comprises a means for adjusting the intensity of the light pulse emitted by the light source to between about 0.01 cd/m to about 999 cd/m". In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of about 10 cd/m .
[0093] In some embodiments, the PLR measurement system comprises a means for adjusting the intensity of the light pulse emitted by the light source to between about 0.01 lux to about 999 lux. In some embodiments, the intensity of the light pulse emitted by the light source is adjustable in increments of about 10 lux.
[0094] In some embodiments, the power of the light source is adjustable. In some embodiments, the PLR measurement system further comprises a potentiometer for adjusting the intensity of the light pulse emitted by the light source. In some embodiments, the PLR measurement system further comprises an optical filter capable of adjusting intensity of the light pulse emitted by the source. In some embodiments, the optical filter that adjusts intensity of the light pulse is a neutral density (ND) filter. In some embodiments, the optical filter that adjusts intensity of the light pulse is ND-filter wheel.
Eye Cover
[0095] In some embodiments, the PLR measurement system further comprises body that operatively covers the eye and blocks light (an "eye cover"). In some embodiments, the eye cover is a pair of glasses or goggles. In some embodiments, the eye cover is operatively connected to the light source.
Head Support
[0096] In some embodiments, the PLR measurement system further comprises a body that supports the head of the subject. In some embodiments, the support is a chin rest.
Computer-Processing Device
[0097] In some embodiments, the PLR measurement system further comprise a computer- processing device, optionally connected to a computer network. In some embodiments, the PLR measurement system further comprises a software module executed by the computer-processing device to analyze pupillary light response in a subject. In some embodiments, the PLR measurement system further comprises a software module executed by the computer-processing device to compare the pupillary light response in the subject to a standard or control. In some embodiments, the PLR measurement system further comprises a support, for example a chin rest upon which the chin of the subject rests during pupillometry. In some embodiments, the position of the support is adjustable relative to the light source and camera. In some embodiments, the position of the light source and camera are adjustable relative to the support.
Digital Processing Device
[0098] In some embodiments, the PLR measurement systems further comprise a digital processing device, or use of the same. In further embodiments, the digital processing device includes one or more hardware central processing units (CPU) that carry out the device's functions. In still further embodiments, the digital processing device further comprises an operating system configured to perform executable instructions. In some embodiments, the digital processing device is optionally connected a computer network. In further embodiments, the digital processing device is optionally connected to the Internet such that it accesses the World Wide Web. In still further embodiments, the digital processing device is optionally connected to a cloud computing infrastructure. In other embodiments, the digital processing device is optionally connected to an intranet. In other embodiments, the digital processing device is optionally connected to a data storage device.
[0099] In accordance with the description herein, suitable digital processing devices include, by way of non-limiting examples, server computers, desktop computers, laptop computers, notebook computers, sub-notebook computers, netbook computers, netpad computers, set-top computers, handheld computers, Internet appliances, mobile smartphones, tablet computers, personal digital assistants, video game consoles, and vehicles. Those of skill in the art will recognize that many smartphones are suitable for use in the system described herein. Those of skill in the art will also recognize that select televisions, video players, and digital music players with optional computer network connectivity are suitable for use in the system described herein. Suitable tablet computers include those with booklet, slate, and convertible configurations, known to those of skill in the art.
[00100] In some embodiments, the digital processing device includes an operating system configured to perform executable instructions. The operating system is, for example, software, including programs and data, which manages the device's hardware and provides services for execution of applications. Those of skill in the art will recognize that suitable server operating systems include, by way of non-limiting examples, FreeBSD, OpenBSD, NetBSD®, Linux, Apple® Mac OS X Server®, Oracle® Solaris®, Windows Server®, and Novell® NetWare®. Those of skill in the art will recognize that suitable personal computer operating systems include, by way of non-limiting examples, Microsoft® Windows®, Apple® Mac OS X®, UNIX®, and UNIX- like operating systems such as GNU/Linux®. In some embodiments, the operating system is provided by cloud computing. Those of skill in the art will also recognize that suitable mobile smart phone operating systems include, by way of non-limiting examples, Nokia® Symbian® OS, Apple® iOS®, Research In Motion® BlackBerry OS®, Google® Android®, Microsoft® Windows Phone® OS, Microsoft® Windows Mobile® OS, Linux®, and Palm® WebOS®.
[00101] In some embodiments, the device includes a storage and/or memory device. The storage and/or memory device is one or more physical apparatuses used to store data or programs on a temporary or permanent basis. In some embodiments, the device is volatile memory and requires power to maintain stored information. In some embodiments, the device is non- volatile memory and retains stored information when the digital processing device is not powered. In further embodiments, the non-volatile memory comprises flash memory. In some embodiments, the non-volatile memory comprises dynamic random-access memory (DRAM). In some embodiments, the non-volatile memory comprises ferroelectric random access memory (FRAM). In some embodiments, the non-volatile memory comprises phase-change random access memory (PRAM). In other embodiments, the device is a storage device including, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, magnetic disk drives, magnetic tapes drives, optical disk drives, and cloud computing based storage. In further embodiments, the storage and/or memory device is a combination of devices such as those disclosed herein.
[00102] In some embodiments, the digital processing device includes a display to send visual information to a user. In some embodiments, the display is a cathode ray tube (CRT). In some embodiments, the display is a liquid crystal display (LCD). In further embodiments, the display is a thin film transistor liquid crystal display (TFT-LCD). In some embodiments, the display is an organic light emitting diode (OLED) display. In various further embodiments, on OLED display is a passive-matrix OLED (PMOLED) or active-matrix OLED (AMOLED) display. In some embodiments, the display is a plasma display. In other embodiments, the display is a video projector. In still further embodiments, the display is a combination of devices such as those disclosed herein.
[00103] In some embodiments, the digital processing device includes an input device to receive information from a user. In some embodiments, the input device is a keyboard. In some embodiments, the input device is a pointing device including, by way of non-limiting examples, a mouse, trackball, track pad, joystick, game controller, or stylus. In some embodiments, the input device is a touch screen or a multi-touch screen. In other embodiments, the input device is a microphone to capture voice or other sound input. In other embodiments, the input device is a video camera or other sensor to capture motion or visual input. In further embodiments, the input device is a Kinect, Leap Motion, or the like. In still further embodiments, the input device is a combination of devices such as those disclosed herein.
Non-transitory computer readable storage medium
[00104] In some embodiments, the PLR measurement systems further comprise one or more non-transitory computer readable storage media encoded with a program including instructions executable by the operating system of an optionally networked digital processing device. In further embodiments, a computer readable storage medium is a tangible component of a digital processing device. In still further embodiments, a computer readable storage medium is optionally removable from a digital processing device. In some embodiments, a computer readable storage medium includes, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, solid state memory, magnetic disk drives, magnetic tape drives, optical disk drives, cloud computing systems and services, and the like. In some cases, the program and instructions are permanently, substantially permanently, semi-permanently, or non-transitorily encoded on the media.
Computer program
[00105] In some embodiments, the platforms, systems, media, and methods disclosed herein include at least one computer program, or use of the same. A computer program includes a sequence of instructions, executable in the digital processing device's CPU, written to perform a specified task. Computer readable instructions may be implemented as program modules, such as functions, objects, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types. In light of the disclosure provided herein, those of skill in the art will recognize that a computer program may be written in various versions of various languages.
[00106] The functionality of the computer readable instructions may be combined or distributed as desired in various environments. In some embodiments, a computer program comprises one sequence of instructions. In some embodiments, a computer program comprises a plurality of sequences of instructions. In some embodiments, a computer program is provided from one location. In other embodiments, a computer program is provided from a plurality of locations. In various embodiments, a computer program includes one or more software modules. In various embodiments, a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add-ins, or add-ons, or combinations thereof.
Web application
[00107] In some embodiments, the PLR measurement systems further comprise a web application. In light of the disclosure provided herein, those of skill in the art will recognize that a web application, in various embodiments, utilizes one or more software frameworks and one or more database systems. In some embodiments, a web application is created upon a software framework such as Microsoft® .NET or Ruby on Rails (RoR). In some embodiments, a web application utilizes one or more database systems including, by way of non-limiting examples, relational, non-relational, object oriented, associative, and XML database systems. In further embodiments, suitable relational database systems include, by way of non-limiting examples, Microsoft® SQL Server, mySQL™, and Oracle®. Those of skill in the art will also recognize that a web application, in various embodiments, is written in one or more versions of one or more languages. A web application may be written in one or more markup languages, presentation definition languages, client-side scripting languages, server-side coding languages, database query languages, or combinations thereof. In some embodiments, a web application is written to some extent in a markup language such as Hypertext Markup Language (HTML), Extensible Hypertext Markup Language (XHTML), or extensible Markup Language (XML). In some embodiments, a web application is written to some extent in a presentation definition language such as Cascading Style Sheets (CSS). In some embodiments, a web application is written to some extent in a client-side scripting language such as Asynchronous Javascript and XML (AJAX), Flash® Actionscript, Javascript, or Silverlight®. In some embodiments, a web application is written to some extent in a server-side coding language such as Active Server Pages (ASP), ColdFusion®, Perl, Java™, JavaServer Pages (JSP), Hypertext Preprocessor (PHP), Python™, Ruby, Tel, Smalltalk, WebDNA®, or Groovy. In some embodiments, a web application is written to some extent in a database query language such as Structured Query Language (SQL). In some embodiments, a web application integrates enterprise server products such as IBM® Lotus Domino®. In some embodiments, a web application includes a media player element. In various further embodiments, a media player element utilizes one or more of many suitable multimedia technologies including, by way of non-limiting examples, Adobe® Flash®, HTML 5, Apple® QuickTime®, Microsoft® Silverlight®, Java™, and Unity®.
Mobile application
[00108] In some embodiments, the PLR measurement systems further comprise a mobile application provided to a mobile digital processing device. In some embodiments, the mobile application is provided to a mobile digital processing device at the time it is manufactured. In other embodiments, the mobile application is provided to a mobile digital processing device via the computer network described herein.
[00109] In view of the disclosure provided herein, a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non- limiting examples, C, C++, C#, Objective-C, Java™, Javascript, Pascal, Object Pascal,
Python™, Ruby, VB.NET, WML, and XHTML/HTML with or without CSS, or combinations thereof.
[00110] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiFlex,
MoSync, and Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.
[00111] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple® App Store, Android™ Market, BlackBerry® App World, App Store for Palm devices, App Catalog for webOS, Windows® Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, and Nintendo® DSi Shop.
Standalone application
[00112] In some embodiments, the PLR measurement systems further comprise a standalone application, which is a program that is run as an independent computer process, not an add-on to an existing process, e.g., not a plug-in. Those of skill in the art will recognize that standalone applications are often compiled. A compiler is a computer program(s) that transforms source code written in a programming language into binary object code such as assembly language or machine code. Suitable compiled programming languages include, by way of non- limiting examples, C, C++, Objective-C, COBOL, Delphi, Eiffel, Java™, Lisp, Python™, Visual Basic, and VB .NET, or combinations thereof. Compilation is often performed, at least in part, to create an executable program. In some embodiments, a computer program includes one or more executable complied applications.
Web browser plug-in
[00113] In some embodiments, the PLR measurement systems further comprise a web browser plug-in. In computing, a plug-in is one or more software components that add specific functionality to a larger software application. Makers of software applications support plug-ins to enable third-party developers to create abilities which extend an application, to support easily adding new features, and to reduce the size of an application. When supported, plug-ins enable customizing the functionality of a software application. For example, plug-ins are commonly used in web browsers to play video, generate interactivity, scan for viruses, and display particular file types. Those of skill in the art will be familiar with several web browser plug-ins including, Adobe® Flash® Player, Microsoft® Silverlight®, and Apple® QuickTime®. In some embodiments, the toolbar comprises one or more web browser extensions, add-ins, or add-ons. In some embodiments, the toolbar comprises one or more explorer bars, tool bands, or desk bands.
[00114] In view of the disclosure provided herein, those of skill in the art will recognize that several plug-in frameworks are available that enable development of plug-ins in various programming languages, including, by way of non-limiting examples, C++, Delphi, Java™, PHP, Python™, and VB .NET, or combinations thereof.
[00115] Web browsers (also called Internet browsers) are software applications, designed for use with network-connected digital processing devices, for retrieving, presenting, and traversing information resources on the World Wide Web. Suitable web browsers include, by way of non-limiting examples, Microsoft® Internet Explorer®, Mozilla® Firefox®, Google® Chrome, Apple® Safari®, Opera Software® Opera®, and KDE Konqueror. In some embodiments, the web browser is a mobile web browser. Mobile web browsers (also called mircrobrowsers, mini-browsers, and wireless browsers) are designed for use on mobile digital processing devices including, by way of non-limiting examples, handheld computers, tablet computers, netbook computers, subnotebook computers, smartphones, music players, personal digital assistants (PDAs), and handheld video game systems. Suitable mobile web browsers include, by way of non-limiting examples, Google® Android® browser, RIM BlackBerry® Browser, Apple® Safari®, Palm® Blazer, Palm® WebOS® Browser, Mozilla® Firefox® for mobile, Microsoft® Internet Explorer® Mobile, Amazon® Kindle® Basic Web, Nokia® Browser, Opera Software® Opera® Mobile, and Sony® PSP™ browser.
Software modules
[00116] In some embodiments, the PLR measurement systems further comprise software, server, and/or database modules, or use of the same. In view of the disclosure provided herein, software modules are created by techniques known to those of skill in the art using machines, software, and languages known to the art. The software modules disclosed herein are
implemented in a multitude of ways. In various embodiments, a software module comprises a file, a section of code, a programming object, a programming structure, or combinations thereof. In further various embodiments, a software module comprises a plurality of files, a plurality of sections of code, a plurality of programming objects, a plurality of programming structures, or combinations thereof. In various embodiments, the one or more software modules comprise, by way of non-limiting examples, a web application, a mobile application, and a standalone application. In some embodiments, software modules are in one computer program or application. In other embodiments, software modules are in more than one computer program or application. In some embodiments, software modules are hosted on one machine. In other embodiments, software modules are hosted on more than one machine. In further embodiments, software modules are hosted on cloud computing platforms. In some embodiments, software modules are hosted on one or more machines in one location. In other embodiments, software modules are hosted on one or more machines in more than one location. Databases
[00117] In some embodiments, the PLR measurement systems further comprise one or more databases, or use of the same. In view of the disclosure provided herein, those of skill in the art will recognize that many databases are suitable for storage and retrieval of image and scoring information. In various embodiments, suitable databases include, by way of non-limiting examples, relational databases, non-relational databases, object oriented databases, object databases, entity-relationship model databases, associative databases, and XML databases. In some embodiments, a database is internet-based. In further embodiments, a database is web- based. In still further embodiments, a database is cloud computing-based. In other embodiments, a database is based on one or more local computer storage devices.
Visual Cycle Modulators
[00118] Disclosed herein, in certain embodiments, are methods of adjusting the dose of a visual cycle modulator in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard; wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; and wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod- mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some embodiments, the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is terminated if the pupillary light response is greater than the standard or control. In some embodiments, the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control. In some embodiments, a drug holiday from the visual cycle modulator is commenced if the pupillary light response is less than the standard or control.
[00119] Disclosed herein, in certain embodiments, are methods of treating an ocular disease or disorder in a subject in need thereof, comprising: (a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) changing or maintaining the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard, wherein the control or standard is: (i) derived from a healthy individual or population of healthy individuals; (ii) derived from an individual or population of individuals who have or have had an ocular disease; or (iii) derived from the subject prior to administration of the visual cycle modulator; wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control. In some embodiments, the methods further comprise isolating the rod-mediated component of PLR. In some embodiments, the methods further comprise isolating the cone-mediated component of PLR. In some embodiments, the methods further comprise isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR. In some
embodiments, the visual cycle modulator is maintained if the pupillary light response is less than the standard or control. In some embodiments, the visual cycle modulator is changed if the pupillary light response is greater than the standard or control. In some embodiments, the ocular disease or disorder is a disease or disorder associated with dysfunction of metabolism of visual retinoids. In some embodiments, the ocular disease or disorder is selected from: Stargardt disease; age-related macular degeneration; cone -rod dystrophy; retinitis pigmentosa (RP);
childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus. In some embodiments, the ocular disease or disorder is photokeratitis.
[00120] In some embodiments, the visual cycle modulator is a modulator of retinol binding protein transthyretin, rhodopsin, all-trans retinol dehydrogenase, lecithin retinol acyltransferase, RPE-specific 65 kDa protein, 11-cis-retinol dehydrogenase, or a combination thereof. In some embodiments, the visual cycle modulator is an inhibitor of a member of the visual cycle. In some embodiments, the visual cycle modulator is in an inhibitor of RPE-specific 65 kDa protein (RPE65). In some embodiments, the inhibitor of RPE65 is emixustat.
[00121] In some embodiments, the visual cycle modulator is a compound of Formula (A), or tautomer, stereoisomer, geometric isomer, N-oxide or a pharmaceutically acceptable salt thereof:
Figure imgf000040_0001
Formula (A) wherein,
X is selected from -C(R9)=C(R9)-, -C≡C- -C(R9)2-0-, -C(R9)2-C(R9)2-, - C(R9)2-S-, -C(R9)2-S(0)2-, or -C(R9)2-NR9-;
Y is selected from:
a) substituted or unsubstituted carbocyclyl, optionally substituted with Q-C4 alkyl, halogen, -OH, or C1-C4 alkoxy;
b) substituted or unsubstituted carbocyclylalkyl, optionally substituted with Cr C4 alkyl, halogen, -OH, or Q-C4 alkoxy;
c) substituted or unsubstituted aralkyl, optionally substituted with C1-C4 alkyl, halogen, -OH, or C1-C4 alkoxy; or
d) substituted or unsubstituted C3-C10 alkyl, optionally substituted with halogen, -OH, or C1-C4 alkoxy;
1 2 1 2
R is hydrogen and R is hydroxyl; or R and R form an oxo; R7 is hydrogen;
Q
R is hydrogen or CH3;
each R9 is independently hydrogen, or a substituted or unsubstituted C1-C4 alkyl; each 33
R is independently selected from halogen, or a substituted or unsubstituted C1-C4 alkyl, and n is 0, 1, 2, 3, or 4.
[00122] In some embodiments, n is 0, 1, or 2.
[00123] In some embodiments, X is -C(R9)=C(R9)-. In some embodiments, X is -C=C-.
In some embodiments, X is -C(R9)2-0-. In some embodiments, X is -C(R9)2-C(R9)2-. In some embodiments, X is -C(R9)2-S-. In some embodiments, X is -C(R9)2-S(0)2-. In some embodiments, X is -C(R9)2-NR9-.
[00124] In some embodiments, Y is substituted or unsubstituted carbocyclyl, or substituted or unsubstituted C3-Cio alkyl. In some embodiments, Y is substituted or
unsubstituted carbocyclyl. In some embodiments, the substituted or unsubstituted carbocyclyl is a substituted or unsubstituted 4-, 5-, 6-, or 7-membered ring. In some embodiments, the substituted or unsubstituted carbocyclyl is a 6-membered ring. In some embodiments, the substituted or unsubstituted 6-membered ring is a substituted or unsubstituted cyclohexyl. In some embodiments, the substituted or unsubstituted 6-membered ring is a substituted or unsubstituted cyclohexyl and X is -C(R9)2-0-.
[00125] In some embodiments, Y is substituted or unsubstituted C3-Cio alkyl. In some embodiments, the substituted or unsubstituted C3-Cio alkyl is a substituted or unsubstituted C3- C6 alkyl. In some embodiments, the substituted C3-C6 alkyl is substituted with an Ci-C2 alkoxy group. In some embodiments, the substituted C3-C6 alkyl is -CH2CH2CH2OCH3. 1 2
[00126] In some embodiments, R is hydrogen and R is hydroxyl. In some embodiments,
1 2 8 8
R and R" form an oxo. In some embodiments, R is hydrogen. In some embodiments, R is
1 2 9
methyl. In some embodiments, R is hydrogen, R is hydroxyl and X is -C(R )2-0-.
[00127] In some embodiments, the visual cycle modulator is a compound, or tautomer, stereoisomer, geometric isomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
[00129] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000044_0002
[00130] In some embodiments, the visual cycle modulator is a compound, or tautomer, stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000044_0003
Figure imgf000045_0001
[00131] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000045_0002
[00132] In some embodiments, the visual cycle modulator a compound, or tautomer, stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000045_0003
[00133] In some embodiments, the visual cycle modulator is a compound, or tautomer, tereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, selected from:
Figure imgf000045_0004
[00134] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0001
[00135] In some embodiments, the visual cycle modulator is a compound, stereoisomer, -oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0002
[00136] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0003
[00137] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0004
[00138] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0005
[00139] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0006
[00140] In some embodiments, the visual cycle modulator is a compound, or stereoisomer, N-oxide or a pharmaceutically acceptable salt thereof, having the structure:
Figure imgf000046_0007
EXAMPLES
[00141] For the examples described herein, Compound A corresponds to (i?)-3-amino-l-
(3-((2-propylpentyl)oxy)phenyl)propan-l-ol.
Example 1: Clinical Trial
[00142] Study Design: Phase 1, single-site, controlled and randomized, open label study
Study objective: To correlate ERG and PLR measurements during treatment with
13- cis retinoic acid
Study Subjects: Normal, healthy adults
Randomization: 40 subjects randomized 1 : 1 : 1 : 1 to placebo, 10 mg, 20 mg, and 40 mg 13 -cis retinoic acid
Study Duration: Daily oral dosing for 14 days with follow-up on day 28
Data Collection: ERG and pupillometry at baseline, Day 7, Day 14 and Day 28
Example 2: Screen for Hereditary Ocular Disease
[00143] Two weeks post birth a female child is screened for signs of an ocular disorder.
The child is fitted with diagnostic device which blocks light. After 10 minutes of complete dark adaptation a 100 millisecond light pulse is flashed. An infrared camera captures the PLR of the child. A physician compares the child's PLR to a control. The child's PLR matches the control.
Example 3: Screen for Hereditary Ocular Disease
[00144] Two weeks post birth a female child is screened for signs of an ocular disorder.
The child is fitted with diagnostic device which blocks light. After 10 minutes of complete dark adaptation a 100 millisecond light pulse is flashed. An infrared camera captures the PLR of the child. A physician compares the child's PLR to a control. The child's PLR is attenuated compared to the control. The child is referred to a pediatric retinal specialist for further evaluation.
Example 4: Screen for Efficacy of Treatment with Emixustat
[00145] An individual diagnosed with geographic atrophy associated with dry AMD is administered a daily dosage of 5 mg of emixustat for 1 month. After 1 month, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. A physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before
administration of emixustat. The physician increases the daily dosage of emixustat to 10 mg.
Example 5: Screen for Efficacy of Treatment with Emixustat
[00146] An individual diagnosed with geographic atrophy associated with dry AMD is administered a daily dosage of 5 mg of emixustat for 1 month. After 1 month, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. A physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before
administration of emixustat. The physician increases the daily dosage of emixustat to 10 mg.
[00147] After a second month of treatment with emixustat, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. The physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before administration of emixustat. The physician increases the daily dosage of emixustat to 15 mg.
[00148] After a third month of treatment with emixustat, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. The physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before administration of emixustat. The physician increases the daily dosage of emixustat to 20 mg.
[00149] After a fourth month of treatment with emixustat, the individual undergoes pupillometry. After 10 minutes of complete dark adaptation, a 50 millisecond light pulse is flashed. A camera captures the PLR of the individual. The physician compares the individual's PLR to a control. The individual's PLR is the same as the PLR before administration of emixustat. The physician halts administration of emixustat.
Example 6: Pupillometry Measurements in Mice:
[00150] Mice were between 6 and 12 weeks old and approximately 25 g each. Animals were dark adapted for a minimum of 12 hours; all subsequent procedures were performed under dim red light. Mice were dosed by oral gavage with Compound A (a representative visual cycle modulator), or vehicle (water), as indicated under dim red light. Six hours after dosing, the pupillary light response (PLR) was recorded. Five minutes prior to PLR recording, mice were anesthetized intraperitoneally with a mixture of ketamine (60mg/kg) and xylazine (6mg/kg). Body temperature was maintained on a heating pad. Eyes were kept moist during pupillometry reading by applying Celluvisc eye drops. Pupillometry readings were recorded using a
Neuroptics A-2000 small animal pupillometer system. This system is equipped with an infrared camera which collects real-time video of changes in pupil size. The PLR was recorded for 5 seconds before and after a 100 ms green light pulse (528 nm). As the software is programed to report lux values, the light intensities for the following experiment is reported in lux units rather than in cd/m . PLR measurements were taken at 8 increasing light intensities: 80 lux, 125 lux, 200 lux, 250 lux, 325 lux, 400 lux, 500 lux, and 630 lux. A 3 minute recovery was allowed between pulses.
[00151] Figure 5 shows the representative mouse PLR data collected using the Neuroptics
A-2000 small animal pupillometer system. The images show video captures of a pupil from an untreated mouse eye at three phases of the PLR: 1) Dark-adapted phase; 2) Constriction phase; and 3) Recovery phase. The graphical tracing below the images is a plot of the pupil size (diameter in mm) as a function of time. Pupil size measurements are recorded every 30 milliseconds during the entire time course (0 - 5 seconds).
[00152] Figure 6 shows the effect of Compound A on the PLR in mice. Dark-adapted mice were treated with drug vehicle (Control; Figure 6A) or Compound A (3 mg/kg or 10 mg/kg; Figures 6B and 6C respectively) 6 hours prior to collecting PLR measurements.
Tracings shown were recorded in darkness (0 lux) or following exposure to a pulse of green light (100 ms, 528 nm). The PLR was recorded at 8 different light intensities (from 80 - 630 lux). Each single trace is an average of data collected from 4 mice (8 eyes). Mice treated with drug vehicle show a light dependent pupil constriction and delay in recovery of the dark-adapted pupil size. Pupil constriction in mice treated with Compound A is less pronounced and shows no dependence on light at higher intensities.
[00153] Figure 7 shows the effect of Compound A on pupil constriction in mice.
Measurements of absolute pupil size at 1 second following each light pulse are shown in the upper panel (Figure 7A). Change in absolute pupil size, relative to the respective dark adapted values at 1 second (0 lux), are shown in the lower panel (Figure 7B). Pupil constriction in mice treated with drug vehicle (n = 4) follows a clear light dependent pattern across all light intensities. In mice treated with Compound A (n = 4), pupil constriction does not demonstrate a light dependent pattern at light intensities above 125 lux. Differences in pupil size between control and drug-treated mice become statistically significant at light intensities of 400 lux and above (*, p<0.05).
[00154] Figure 8 shows the effect of Compound A on recovery of dark-adapted pupil size in mice. Measurements of absolute pupil size at 4.7 seconds following the light pulse are shown (Figure 8A). Change in absolute pupil size, relative to the respective dark adapted values at 4.7 seconds (0 lux), are shown in the lower panel (Figure 8B). In control mice (n = 4), change of the pupil size during the recovery phase shows a light-dependent pattern that is consistent with the PLR constriction data. In mice treated with Compound A (n = 4), recovery to the dark-adapted pupil size is profoundly delayed despite the relatively less significant constriction, compared to control. Differences in change of pupil size during the recovery phase between control and drug- treated mice are statistically significant at the indicated light intensities (*, p<0.05).
Example 7: Recovery of Rod Photoreceptor Activity after Photobleaching Assessed by Electroretinography:
[00155] Recovery of rod photoreceptor activity after photobleaching was assessed by electroretinography (ERG) using the e2 Espion ERG system. Dark adapted (>12 hours) BALB/c mice (8 weeks, n = 4/group) were orally dosed with Compound A (3 or 10 mg/kg) or vehicle (water). Mice remained in the dark and ERG measurements were performed 6 hours after treatment. Ten minutes before ERG measurements were made, mice were anesthetized with Ketamine:Xylazine (100: 10 mg/kg) in PBS (intraperitoneal, i.p., injection; 4 μΕ/g). Left eyes were dilated with 1 drop of 0.5% tropicamide. All measurements were taken in a dark room under dim red light. Pre bleach recordings in response to 0.01 cd*s/m2 (n = 5 measurements) were assessed after a 5 minute recovery from red light exposure. Mice were photobleached (400 cd/m2, 30 sec) and scotopic ERG b wave responses (amplitudes in μν) to 0.01 cd*s/m2 stimuli were recorded every 2 minutes for 50 minutes.
[00156] Figure 9 shows the effect of Compound A on rod photoreceptor activity. The recovery of rod photoreceptor function following a photobleach was measured by ERG. Mice were treated with drug vehicle or Compound A (3 mg/kg or 10 mg/kg; n = 4/dose group) and ERG responses were recorded every 2 minutes for 50 minutes using a light stimulus 0.01 cd*s/m2. Rod photoreceptor-derived b-wave amplitudes are plotted as a function of recovery time after photobleach. B-wave response amplitudes (μν), at each corresponding time point of recovery, are shown as mean values ± SEM for each of the treatment groups. Treatment with Compound A produced a dose-dependent suppression of b-wave response amplitudes.
[00157] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A method of adjusting the dose of a visual cycle modulator in a subject in need thereof, comprising:
(a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and
(b) adjusting the dose of the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard;
wherein the control or standard is:
i) derived from a healthy individual or population of healthy individuals; ii) derived from an individual or population of individuals who have or have had an ocular disease; or
iii) derived from the subject prior to administration of the visual cycle modulator; and
wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
2. A method of diagnosing a subject as having or being predisposed to develop an ocular
disease or disorder, comprising:
(a) comparing pupillary light response (PLR) in an eye of the subject to a control or standard; and
(b) diagnosing the subject as having or being predisposed to develop an ocular disease or disorder if the pupillary light response in the subject deviates from the control or standard;
wherein the control or standard is:
i) derived from a healthy individual or population of healthy individuals; or
ii) derived from an individual or population of individuals who have or have had an ocular disease; and
wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
3. A method of treating an ocular disease or disorder in a subject in need thereof, comprising:
(a) comparing pupillary light response (PLR) in a subject following administration of a visual cycle modulator to the subject to a control or standard; and (b) changing or maintaining the visual cycle modulator if the pupillary light response in the subject deviates from the control or standard,
wherein the control or standard is:
i) derived from a healthy individual or population of healthy individuals;
ii) derived from an individual or population of individuals who have or have had an ocular disease; or
iii) derived from the subject prior to administration of the visual cycle modulator;
wherein a software module executed by a computer processing device analyzes the pupillary light response in the subject and compares the pupillary light response in the subject to the standard or control.
4. The method of any of claims 1-3, further comprising isolating the rod-mediated component of PLR.
5. The method of any of claims 1-3, further comprising isolating the cone -mediated component of PLR.
6. The method of any of claims 1-3, further comprising isolating the melanopsin-containing retinal ganglion cells-mediated component of PLR
7. The method of claim 1, wherein the dosage of the visual cycle modulator is increased if the pupillary light response is greater than the standard or control.
8. The method of claim 1 , wherein a drug holiday from the visual cycle modulator is
terminated if the pupillary light response is greater than the standard or control.
9. The method of claim 1, wherein the dosage of the visual cycle modulator is decreased if the pupillary light response is less than the standard or control.
10. The method of claim 1, wherein a drug holiday from the visual cycle modulator is
commenced if the pupillary light response is less than the standard or control.
11. The method of claim 2, wherein greater suppression of pupillary light response as compared to the standard or control is indicative of an increased likelihood of having or developing an ocular disease or disorder.
12. The method of claim 3, wherein the visual cycle modulator is maintained if the pupillary light response is less than the standard or control.
13. The method of claim 3, wherein the visual cycle modulator is changed if the pupillary light response is greater than the standard or control.
14. The method of any of claims 1-3, comprising exposing the individual to the light pulse for about 50 to about 100 milliseconds.
15. The method of any of claims 1-3, wherein measuring PLR comprises measuring rate of constriction of the pupil, rate of recovery of the pupil, minimum pupil diameter, and duration of constriction.
16. The method of any of claims 1-3, further comprising measuring the diameter of the dark- adapted pupil.
17. The method of any of claims 1-3, further comprising isolating the pupil of the subject from light for a period of time sufficient for the pupil to become dark-adapted.
18. The method of any of claims 1-3, further comprising isolating the pupil of the subject from light for at least 10 minutes.
19. The method of any of claims 1-3, further comprising isolating the pupil of the subject from light for greater than 10 minutes.
20. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 375 nm to about 450 nm.
21. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 450 nm to about 525 nm.
22. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 525 nm to about 575 nm.
23. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 600 nm to about 700 nm.
24. The method of any of claims 1-3, wherein intensity of the light pulse is between about -2 log
2 2
cd/m to about 2 log cd/m .
25. The method of claim 24, comprising adjusting the intensity of the light pulse by increments of about 1 log cd/m .
26. The method of any of claims 1-3, wherein intensity of the light pulse is between about 0.01 cd/m2 to about 999 cd/m2.
27. The method of claim 26, comprising adjusting the intensity of the light pulse by increments of about 10 cd/m .
28. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 375 nm to about 450 nm and intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m .
29. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 450 nm to about 525 nm and intensity of the light pulse is between about -2 log cd/m to
2
about 2 log cd/m .
30. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m .
31. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about -2 log cd/m to about 2 log cd/m .
32. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 375 nm to about 450 nm and intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m2.
33. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 450 nm to about 525 nm and intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m2.
34. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 525 nm to about 575 nm and intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m2.
35. The method of any of claims 1-3, wherein the wavelength of the light pulse is from about 600 nm to about 700 nm and intensity of the light pulse is between about 0.01 cd/m to about 999 cd/m2.
36. The method of any of claims 1-3, further comprising capturing images of the PLR before, during and after exposure to the light pulse.
37. The method of claim 36, wherein the images are captured with a camera.
38. The method of claim 36, wherein the images are continuous.
39. The method of claim 36, wherein the images are discrete.
40. The method of claim 36, wherein the camera is an infrared camera.
41. The method of claim 2 or claim 3, wherein the ocular disease or disorder is a disease or
disorder associated with dysfunction of metabolism of visual retinoids.
42. The method of claim 2 or claim 3, wherein the ocular disease or disorder is selected from:
Stargardt disease; age-related macular degeneration; cone-rod dystrophy; retinitis pigmentosa (RP); childhood onset severe retinal dystrophy; early onset severe retinal dystrophy; Leber congenital amaurosis (LCA); retinitis punctata albescens; Bothnia dystrophy; and fundus albipunctatus.
43. The method of claim 2 or claim 3, wherein the ocular disease or disorder is photokeratitis.
44. The method of claim 1 or claim 3, wherein the visual cycle modulator is emixustat,
Figure imgf000055_0001
emixustat,
or a salt thereof.
45. The method of claim 44, wherein the visual cycle modulator is emixustat HC1.
46. A system for measuring pupillary light response (PLR), comprising (a) a light source that emits a light pulse, (b) a camera capable of capturing images of a pupil before, during and after exposure of the pupil to a light source; and (c) a software module executed by a computer processing device that analyzes pupillary light response of a subject and compares the pupillary light response to a standard or control.
47. The system of claim 46, wherein the light source is an incandescent light source.
48. The system of claim 46, wherein the light source is a halogen light source.
49. The system of claim 46, wherein the light source is a LED light source.
50. The system of claim 46, wherein the light source is a luminescent light source.
51. The system of claim 46, wherein the light source is a fluorescent light source
52. The system of claim 46, wherein the light source emits a light pulse having a wavelength from about 375 nm to about 450 nm.
53. The system of claim 46, wherein the light source emits a light pulse having a wavelength from about 450 nm to about 525 nm.
54. The system of claim 46, wherein the light source emits a light pulse having a wavelength from about 525 nm to about 575 nm.
55. The system of claim 46, wherein the light source emits a light pulse having a wavelength from about 600 nm to about 700 nm.
56. The system of claim 46, wherein the intensity of the light pulse emitted by the light source is between about -2 log cd/m 2 to about 2 log cd/m 2.
57. The system of claim 46, wherein the intensity of the light pulse emitted by the light source is
2 2
between about 0.01 cd/m to about 999 cd/m .
58. The system of claim 46, further comprising an optical filter that emits light of a wavelength from about 375 nm to about 450 nm.
59. The system of claim 46, further comprising an optical filter that emits light of a wavelength from about 450 nm to about 525 nm.
60. The system of claim 46, further comprising an optical filter that emits light of a wavelength from about 525 nm to about 575 nm.
61. The system of claim 46, further comprising an optical filter that emits light of a wavelength from about 600 nm to about 700 nm.
62. The system of any one of claims 58-61, wherein the optical filter is an absorptive optical filter, dichroic optical filter, or monochromatic optical filter.
63. The system of any one of claims 58-61, wherein the optical filter is an optical filter wheel which emits a light wavelength selection between 400 - 700 nm, in 10 - 25 nm increments.
64. The system of any one of claims 58-61, wherein the optical filter is an optical filter wheel which emits a light wavelength selection between 500 - 700 nm, in 10 - 25 nm increments.
65. The system of claim 46, further comprising a potentiometer that adjusts the intensity of light pulse.
66. The system of claim 65, further comprising a potentiometer that adjusts the intensity of light pulse in increments of 1 log cd/m .
67. The system of claim 65, further comprising a potentiometer that adjusts the intensity of light pulse in increments of 10 cd/m
68. The system of claim 46, further comprising an optical filter that adjusts the intensity of the light pulse.
69. The system of claim 46, further comprising an optical filter that adjusts the intensity of the light pulse between about -2 log cd/m 2 to about 2 log cd/m 2.
70. The system of claim 46, further comprising an optical filter that adjusts the intensity of the light pulse between about 0.01 cd/m 2 to about 999 cd/m 2.
71. The system of claim 68 or claim 69, wherein the optical filter adjusts the intensity of the light pulse in increments of 1 log cd/m .
72. The system of claim 68 or claim 70, wherein the optical filter adjusts the intensity of the light pulse in increments of 10 cd/m .
73. The system of claim 46, wherein the power of the light pulse is adjustable.
74. The system of claim 46, wherein the camera is an infrared camera.
75. The system of claim 46, wherein the camera is capable of capturing a series of continuous images.
76. The system of claim 46, wherein the camera is capable of capturing a series of discrete
images.
77. The system of claim 46, wherein the computer-processing device is connected to a computer network.
78. The system of claim 46, further comprising electronic memory for storing the images.
79. The system of claim 46, wherein further comprising a body that operatively covers the eye and blocks light.
80. The system of claim 79, wherein the body that operatively covers the eye and blocks light is a pair of glasses or goggles.
81. The system of claim 79, wherein the body that operatively covers the eye and blocks light is operatively connected to the light source.
82. The system of claim 46, wherein further comprising body that supports the head of the
subject.
83. The system of claim 82, wherein the support is a chin rest.
84. The system of claim 82, wherein the position of the support is adjustable relative to the light source and camera.
85. The system of claim 82, wherein the position of the light source and camera are adjustable relative to the support.
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