Fuchs Dystrophy: A New Paradigm in Diagnosis and Treatment David G. - - PowerPoint PPT Presentation

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Fuchs Dystrophy: A New Paradigm in Diagnosis and Treatment David G. - - PowerPoint PPT Presentation

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Fuchs Dystrophy: A New Paradigm in Diagnosis and Treatment David G. Hwang, MD, FACS Professor and Vice Chair Kimura Endowed Chair in Ophthalmology Director, Cornea Service and Refractive Surgery Services University of California, San Francisco

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Hwang/UCSF

Fuchs Dystrophy:

A New Paradigm in Diagnosis and Treatment David G. Hwang, MD, FACS

Professor and Vice Chair Kimura Endowed Chair in Ophthalmology Director, Cornea Service and Refractive Surgery Services University of California, San Francisco

December 2016

Hwang/UCSF

Disclosure

Shire – Consultant None of the above are relevant to this talk. I have no proprietary interest in any devices, drugs, or techniques discussed.

Hwang/UCSF

Fuchs Dystrophy

  • Genetics and Pathogenesis

– Molecular genetics and pathogenesis – Diagnosis and prognosis

  • Treatment

– Surgical therapy: DMEK – Medical therapy targets

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Fuchs Dystrophy

  • Genetics and Pathogenesis

– Molecular genetics and pathogenesis – Diagnosis and prognosis

  • Treatment

– Surgical therapy: DMEK – Medical therapy targets

Hwang/UCSF

Fuchs Dystrophy

  • Leading cause of corneal visual loss

– 30% of US corneal transplants (14,000/year) – Visual loss due to corneal edema and/or guttata

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Fuchs Genetics

  • Minor forms of Fuchs caused by

mutations in

– COL8A, ZEB1, SLC4A11

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CTG Expansion Causes Fuchs

  • Trinucleotide repeat (CTG) expansion in TCF4

(transcription factor 4) intron (Wieben, 2012) – 25-73% Fuchs – 0-5% controls – More repeats = more severe disease

(Soliman, 2015)

Vasanth S. IOVS 2015:56:4531-4536

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> 50 CTG Repeats Correlates with Clinical Diagnosis of Fuchs

Vasanth S. IOVS 2015:56:4531-4536

50 CTG Controls Fuchs Dystrophy

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Molecular Pathogenesis

  • Transcription of CTG repeats creates

poly(CUG) RNA

  • Poly(CUG) RNA sequesters MBNL1, a

RNA splicing factor (Du, 2015)

  • Splicing errors cause dysregulated

transcription and accumulate toxic RNA

(Mootha, 2016)

  • Non-ATG translation of expansion

repeats has been shown to create toxic homopolymeric proteins (Zu, 2011)

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MBNL1 and (CUG)n RNA Co-Localize

Du J. J Biol Chem 2015;290:5979-5990

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Trinucleotide Repeat Diseases

  • CAG

– Huntington’s disease, spinocerebellar ataxia

  • CTG

– Myotonic dystrophy, Fuchs dystrophy

  • Other

– Fragile X syndrome, Friedreich ataxia

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Polymerase Slippage – Hairpin Loop

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Trinucleotide Repeat Diseases

  • Looped hairpin is stabilized by the G and

C nucleotides in the repeat

CTGCTGCTG GTCGTCGTC

  • Loop repair may excise (contract) or

incorporate (expand) the repeat segment

  • Above 35 repeats, the TNR expansion

segment tends to persist/elongate

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Implications

  • Molecular diagnostic testing for Fuchs

could have clinical relevance

– diagnosis – risk profile assessment

  • Understanding of pathogenesis can

yield potential therapeutic targets

Hwang/UCSF

Fuchs Dystrophy

  • Genetics and Pathogenesis

– Molecular genetics and pathogenesis – Diagnosis and prognosis

  • Treatment

– Surgical therapy: DMEK – Medical therapy targets

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Fuchs Dystrophy

  • Genetics and Pathogenesis

– Molecular genetics and pathogenesis – Diagnosis and prognosis

  • Treatment

– Surgical therapy: DMEK – Medical therapy targets

Hwang/UCSF

Endokeratoplasty is Treatment of Choice for Fuchs Dystrophy

  • DSAEK – Descemet Stripping

Automated Endothelial Keratoplasty

– posterior stroma + endo (80-200 µ)

  • DMEK – Descemet Membrane

Endothelial Keratoplasty

– DM + endo (20 µ)

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PK DLEK DSEK DSAEK DMEK 21,620 21,211 344 2011 21,422 22,301 748 2012

US Data, EBAA 2015 Annual Statistical Report

Evolution of Keratoplasty ?

20,954 23,465 1522 2013 19,294 23,100 2865 2014

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Hwang/UCSF Hwang/UCSF

DSAEK DMEK

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DSAEK DMEK 20/25- 20/25+

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Clinical Outcomes

  • 94% of patients achieve 20/40 or better

BSCVA by 3 months

– 63-80% 20/25 – 26-44% 20/20

  • Compare 12% 20/20 for ultrathin

DSAEK

  • Fewer higher-order aberrations

Price MO, Ophthalmology 2009; NIIOS 2015, World Cornea Congress; Busin M, Am J Ophthalmology 2013

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DMEK vs DSAEK

  • Speed of visual recovery

✓ ✓ ✓ ✓ DMEK 26%-44% 20/20 at 3 mo UT-DSAEK 12% 20/20 at 3 mo

Hwang/UCSF Price MO, Ophthalmology 2009; Busin M, Am J Ophthalmology 2013

DMEK vs DSAEK

  • Endothelial cell density

✓ ✓ ✓ ✓ DMEK (16% loss at 6 mo.) UT-DSAEK (36% loss at 6 mo., p < 0.05)

Hwang/UCSF Goldich Y . Am J Ophthalmol 2015; 159:155-159.

DMEK vs DSAEK

  • Primary Graft Failure

✓ ✓ ✓ ✓ DMEK (1.4%) UT-DSAEK (3.9%)

Hwang/UCSF Busin M. Iophthalmology 2013;120:1186-94. Circovic A. Cornea 2015;34:11-17.

DMEK vs DSAEK

  • Rejection: 2-year rates

✓ ✓ ✓ ✓ DMEK (1%) UT-DSAEK (3.3%)

Hwang/UCSF Anshu A. Ophthalmology 2012;110:536-40; Busin M. Ophthalmology 2013;120:1186-94.

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DMEK vs DSAEK

  • Rejection: 2 year rates

✓ ✓ ✓ ✓ DMEK (1%) UT-DSAEK (3.3%) vs: conventional DSAEK (7-12%)

Hwang/UCSF Anshu A. Ophthalmology 2012;110:536-40; Busin M. Ophthalmology 2013;120:1186-94.

DMEK vs DSAEK

  • Patient satisfaction

DMEK UT-DSAEK

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DMEK vs DSAEK

  • Patient satisfaction

✓ ✓ ✓ ✓ DMEK UT-DSAEK

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DMEK vs DSAEK

  • Patient satisfaction

– In two DMEK vs. DSAEK contralateral studies – Satisfaction score: DMEK > DSAEK (Goldich) – 9/10 prefer DMEK (Maier)

Hwang/UCSF Goldich Y. Am J Ophthalmol 2015; 2014 Oct 14 epub ahead of print Maier AK. Eye 2014 Nov 21 epub ahead of print

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Advantages

UT-DSAEK DMEK Donor preparation Speed of visual recovery Graft deployment Endothelial cell loss Rebubble rate Primary graft failure Learning curve Allograft rejection rate Patient satisfaction

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My EK Algorithm

  • DMEK ideal for

Fuchs dystrophy or mod. corneal edema Uncomplicated anatomy Visual potential of 20/20 Preop vision 20/60 or better

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My EK Algorithm

  • Ultrathin DSAEK ideal for

Severe corneal edema Tubes, iris defects, absent post. capsule Status post vitrectomy Visual potential of 20/25 or worse Preop vision 20/70 - CF

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My EK Algorithm

  • Reserve PK for

Concurrent stromal scarring Need for combined vitreoretinal surgery Flat or absent anterior chamber requiring open sky reconstruction Inability to comply with postop positioning Visual potential of 20/200 or worse Preop vision HM - LP

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DSAEK DMEK 20/25- 20/20-

DSAEK vs. DMEK

2009 2014

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Medical Therapy for Fuchs?

  • Understanding of molecular pathogenesis

yields a variety of potential therapeutic targets to slow / halt progression

  • Promotion of wound healing/repair is

another potential treatment avenue

  • Rho kinase has been shown to promote

corneal endothelial wound repair

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Rho-Kinase Inhibitors in Fuchs

Koizumi N. Cornea 2013;32:1167-70

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Rho-Kinase Inhibitors in Fuchs

Koizumi N. Cornea 2013;32:1167-70

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Koizumi N. Cornea 2013;32:1167-70

Rho-Kinase Inhibitors in Fuchs

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Conclusions

  • The CTG repeat expansion mutation in

TCF4 is the major cause of Fuchs

  • DMEK is an attractive option for surgical

treatment of Fuchs

  • Improved understanding of pathogenesis is

leading to exploration of medical therapy for Fuchs dystrophy

Questions? david.hwang@ucsf.edu

Hwang/UCSF

Thank You

Hwang/UCSF

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