Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Pharmacological Aspects of Myopia

Christine Wildsoet

University of California Berkeley

Myopia: Strategies for the 21st Century

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Pharmacological intervention

- not a very new idea

Bedrossian atropine study (1966)Underlying assumption

Excessive near work involvedExcessive accommodation

implicated

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Bedrossian (1966) Study1% atropine nightlyage 7-13 yr progressing myopesrefractions only

Swap overtime

Incr. progression

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Pharmacological intervention

- options for treatment

Determining factors Is myopia genetic &/or nonvisual?Are visual factors involved?

Scleral target

Retinal (& higher level) target

Animal models

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Animal models Lesson from Bedrossian:Measure eye length + refractive errors

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Drug options - Results from experimental studies & clinical

trials

Main focus of studies Dopaminergic agonists Antimuscarinic drugs

Recent focus of attention Nicotinic drugs NO analogs Retinoic acid Glucagonergic analogs GABA analogs

Others studiedbFGFTNF-VIPMelatoninEnkephalins

Retina - target for many studies!

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Issues to consider in animal-based drug studies

Form deprivation myopia paradigm mostly commonly used

Form deprivation myopia & lens-induced myopia may involve different mechanisms

Intravitreal injection most common route of adminstration Relevance of studies

to human myopia?

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

The retina as a drug targetMany transmitters, many drug

options!

Amacrine cells & their transmitters of particular interest

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

DA analogs - First to be tested with animal modelsRationale

DA regulates retinal coupling

DA influences retinal spatial processing

Low retinal DA

High retinal DA

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Dopamine analogs - Summary of observed effects

dopamine agonists inhibit myopia developmentchickmonkey Key work in this area

Stone, Laties & Tigges (chicks & monkeys)Schaeffel lab (chicks)Stell lab (chicks)Wildsoet & Schmid (chicks)Seko (chicks)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

DA analogs - The earliest study?Chicks & form deprivation myopia

Stone et al.Proc Nat Acad Sci (1989)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Apomorphine & chicks Effects on lens-induced myopia

Schmid & WildsoetARVO (1998)

-15 D lenses: worn from 8 days for 4 days

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Apomorphine, FDM & monkeys

Tigges et al. Invest Ophthalmol Vis Sci (1991)

Form deprived (FD) 5-8 monthswith opaque contact lenses

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Apomorphine, RPE & scleral growth in chick

Seko et al. Cell, Biochemistry & Function (1997)

Retinal pigment epitheium cultured with scleral chondrocytes +/- apomorphine

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Dopaminergic effects - Some apparent inconsistencies

dopamine turnover decreases in FDM & LIMBUT dopamine antagonists can also inhibit eye

growth agonists+antagonists enhance myopia 6-OHDA inhibits FDM, not LIM reserpine inhibits both FDM & LIM

FDM: form deprivation myopiaLIM: lens induced myopia

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Antimuscarinic drugs - Summary of observed effects

Antimuscarinic drugs inhibit myopia developmentchicks tree shrewsmonkeyshumans

Key work in this areaStone, Laties & Tigges (chicks/monkeys)Schaeffel lab (chicks)McBrien lab (chicks & tree shrews)Wildsoet & Schmid (chicks)Wallman lab (chicks)Shih (chicks)SERI (chicks)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Antimuscarinic drugs - Important insight from chick

Ach receptors on chick ciliary musclesare nicotinic!

Ciliary muscle is not the site of actionAccommodation not the target!

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Antimuscarinic drugs -the earliest chick study

Stone et al. Exp Eye Res (1991)

Lid suture for 2 weeks +daily SC injections

Atropine (Atr, nonselective)Pirenzepine (Pir; M1)Methoctramine (Met; M2)4-DAMP (DAMP, M3)

Increasing dose

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

M4-selective antimuscarinic drugs also work!

Cottriall et al. NeuroReport (2001)

Chicks were form deprived & treated with himbacine, a M4 selective agent

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Atropine & lens-induced myopia in chicks

Wildsoet, McBrien & ClarkARVO (1994)

Intravitreal injections25 ug atropine every other day;measured after 7 days

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Antimuscarinic drugs - They also work in mammals &

primates

Tigges et al. Optom Vis Sci (1999)

Monkey

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

DA analogs + antimuscarinic drugs

Can they be combined to improve efficacy?

Schmid & Wildsoet Proc Aust Neurosci Soc (2000)

Chicks: treated from day 8 - day 12

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

DA - Ach analog interactions Another perspective from DFP

Cottriall & McBrien NS Arch Pharm (2001)

Chicks form deprived & injected i.vit. with 2 ug DFP every other day +/-DA antagonists

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Retinally-active drugs -Other possibilities

Nicotinic analogsNOS inhibitors

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Nicotinic analogs & myopia in chicks

Stone et al.Invest Ophthalmol Vis Sci

(2001)

Chicks form-deprived

CHL: chlorisondamineMEC: mecamylamineMLA: methyllcaconitineDHBE: dihyrdo--erythroidine

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Nitric oxide analogs - Inhibition via a retinal pathway?

Fujikado et al.Ophthalmic Res (2001)

Chicks treated with 180 mM l-NAME & -16 D lens (significant effects observed at doses>60 mM)

l-NAME inhibitsoscillatorypotentials

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Retinally-active drugs “work” They tell us about

mechanisms BUT

How safe is the retina as a site of action for myopia

control?

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

The neglected targets - IOP, scleral growth & ocular rhythms

Targeted drugs timolol latanoprost melatonin

Scleral structure(collagen, extracellular matrix) IOP

Scleralcompliance

Eye growth

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

IOP, timolol & myopia control in chicks

-15 D lens Diffusers

IOP decrease 8-10%, FDM; 13-14% LIMSchmid et al. Exp Eye Res (2001)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Latanoprost & myopia inhibition

in chicks - Effect via IOP (or PGs)?

Jin & Stjernschantz Acta Ophthalmol Scand (2000)

Form-deprived for 1 week

BID

BID

X2, separated by 3 days

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

The sclera - An alternative site of action for myopia control drugs?

Curtin, 1985

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

-xyloside study Inhibition PG synthesis in chicks

Rada et al. Exp Eye Res (2002)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

The sclera - An alternative site of action for

antimuscarinic drugs?

EvidenceECMA lesionscell culture

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

ECMA lesions, atropine & myopia in chicks

Fischer et al. Brain Res (1998)

Chicks treated with 25 nmol ECMA, +/- form deprivation & 40 ug atropine daily for 6 days

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Scleral cell culture & myopia in chicks

Lind et al. Invest Ophthal Vis Sci (1998)

Sulfate incorporation by chondrocytes

Atr: atropinePir: PirenzepineDAMP: 4-DAMP

Thymidine incorporation

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

So what about humans?

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Timolol - Not effective for human myopia

control!

JensenActa Ophthalmologica (1991)

0.25% timolol, BID

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Atropine & human myopiaRecent findings are promising!

Shih et al.Acta Ophthalmol Scand (2001)

Refraction changes over 18 months - 0.25% atropine + multifocals cf. multifocal & single vision spectacles

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Pirenzepine & human myopia

Rumor has it that results from on-going trials are very

promising!

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

But is it just that simple?

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Required treatment is very long term chronically applied topical drugs cause

ocular surface disease &/or allergies chronically applied drugs cause tolerance

Target group is young a retinal target site carries inherent risks

Questions to consider Is there a better (safer) site - Yes, sclera? Are there alternative routes of administration? Are there other nonclassical drug options?

Myopia control treatment - There are significant unresolved

issues

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Is oral administration a possibility?

Pirenzepine works in chicks

Flitcroft, Troilo & Wildsoet 8th International Myopia Meeting

(2000)

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Other drug options - Retinoic acid & effects on eye

growth

Mertz & Wallman Exp Eye Res (2001)

Chick scleral punches assayed in culture

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Antisense drugs & eye growth control in

chicks

McGuire & Stell (2000)

Control 2hr treated

Fos-labelling

AODN: antisense oligodeoxynucleotide

Christine Wildsoet, OD, PhD • UC Berkeley Optometry • vision.berkeley.edu/VSP/CW • wildsoet@spectacle.berkeley.edu

Drugs for myopia control

The best way forward?