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 Fuchs Dystrophy • Genetics and Pathogenesis – Molecular genetics and pathogenesis Shire – Consultant – Diagnosis and prognosis • Treatment None of the above are relevant to this talk. – Surgical therapy: DMEK I have no proprietary interest in any devices, – Medical therapy targets drugs, or techniques discussed. Hwang/UCSF Hwang/UCSF 1
Fuchs Dystrophy Fuchs Dystrophy • Genetics and Pathogenesis • Leading cause of corneal visual loss – Molecular genetics and pathogenesis – 30% of US corneal transplants (14,000/year) – Diagnosis and prognosis – Visual loss due to corneal edema and/or guttata • Treatment – Surgical therapy: DMEK – Medical therapy targets Hwang/UCSF Hwang/UCSF Fuchs Genetics CTG Expansion Causes Fuchs • Trinucleotide repeat (CTG) expansion in TCF4 • Minor forms of Fuchs caused by mutations in (transcription factor 4) intron (Wieben, 2012) – COL8A, ZEB1, SLC4A11 – 25-73% Fuchs – 0-5% controls – More repeats = more severe disease (Soliman, 2015) Hwang/UCSF Vasanth S. IOVS 2015:56:4531-4536 Hwang/UCSF 2
> 50 CTG Repeats Correlates Molecular Pathogenesis with Clinical Diagnosis of Fuchs • Transcription of CTG repeats creates poly(CUG) RNA Controls • Poly(CUG) RNA sequesters MBNL1 , a RNA splicing factor (Du, 2015) • Splicing errors cause dysregulated Fuchs Dystrophy transcription and accumulate toxic RNA 50 CTG (Mootha, 2016) • Non-ATG translation of expansion repeats has been shown to create toxic homopolymeric proteins (Zu, 2011) Vasanth S. IOVS 2015:56:4531-4536 Hwang/UCSF Hwang/UCSF MBNL1 and (CUG) n RNA Co-Localize Trinucleotide Repeat Diseases • CAG – Huntington’s disease, spinocerebellar ataxia • CTG – Myotonic dystrophy, Fuchs dystrophy • Other – Fragile X syndrome, Friedreich ataxia Du J. J Biol Chem 2015;290:5979-5990 Hwang/UCSF Hwang/UCSF 3
Polymerase Slippage – Hairpin Loop 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 Hwang/UCSF Hwang/UCSF Implications Fuchs Dystrophy • Molecular diagnostic testing for Fuchs • Genetics and Pathogenesis could have clinical relevance – Molecular genetics and pathogenesis – diagnosis – Diagnosis and prognosis – risk profile assessment • Treatment • Understanding of pathogenesis can – Surgical therapy: DMEK yield potential therapeutic targets – Medical therapy targets Hwang/UCSF Hwang/UCSF 4
Endokeratoplasty is Treatment of Fuchs Dystrophy Choice for Fuchs Dystrophy • Genetics and Pathogenesis • DSAEK – Descemet Stripping – Molecular genetics and pathogenesis Automated Endothelial Keratoplasty – Diagnosis and prognosis – posterior stroma + endo (80-200 µ) • Treatment • DMEK – Descemet Membrane Endothelial Keratoplasty – Surgical therapy: DMEK – DM + endo (20 µ) – Medical therapy targets Hwang/UCSF Hwang/UCSF Evolution of Keratoplasty ? PK DLEK DSEK DSAEK DMEK 2011 21,620 21,211 344 2012 21,422 22,301 748 2013 20,954 23,465 1522 2014 19,294 23,100 2865 Hwang/UCSF Hwang/UCSF US Data, EBAA 2015 Annual Statistical Report 5
DSAEK DMEK Hwang/UCSF Hwang/UCSF 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 DSAEK DMEK • Fewer higher-order aberrations 20/25- 20/25+ Price MO, Ophthalmology 2009; NIIOS 2015, World Cornea Congress; Busin M, Am J Ophthalmology 2013 Hwang/UCSF Hwang/UCSF 6
DMEK vs DSAEK DMEK vs DSAEK ✓ ✓ DMEK ✓ ✓ ✓ DMEK ✓ ✓ ✓ • Speed of visual recovery • Endothelial cell density 26%-44% 20/20 at 3 mo (16% loss at 6 mo.) UT-DSAEK UT-DSAEK (36% loss at 6 mo., p < 0.05 ) 12% 20/20 at 3 mo Goldich Y . Am J Ophthalmol 2015; 159:155-159. Price MO, Ophthalmology 2009; Busin M, Am J Ophthalmology 2013 Hwang/UCSF Hwang/UCSF DMEK vs DSAEK DMEK vs DSAEK ✓ ✓ DMEK ✓ ✓ ✓ DMEK ✓ ✓ ✓ • Primary Graft Failure • Rejection: 2-year rates (1.4%) (1%) UT-DSAEK UT-DSAEK (3.9%) (3.3%) Busin M. Iophthalmology 2013;120:1186-94. Anshu A. Ophthalmology 2012;110:536-40; Busin M. Ophthalmology 2013;120:1186-94. Circovic A. Cornea 2015;34:11-17. Hwang/UCSF Hwang/UCSF 7
DMEK vs DSAEK DMEK vs DSAEK ✓ ✓ DMEK ✓ ✓ • Rejection: 2 year rates • Patient satisfaction DMEK (1%) UT-DSAEK UT-DSAEK (3.3%) vs: conventional DSAEK (7-12%) Anshu A. Ophthalmology 2012;110:536-40; Busin M. Ophthalmology 2013;120:1186-94. Hwang/UCSF Hwang/UCSF DMEK vs DSAEK DMEK vs DSAEK ✓ ✓ DMEK ✓ ✓ • Patient satisfaction • Patient satisfaction – In two DMEK vs. DSAEK contralateral studies UT-DSAEK – Satisfaction score: DMEK > DSAEK (Goldich) – 9/10 prefer DMEK (Maier) Goldich Y. Am J Ophthalmol 2015; 2014 Oct 14 epub ahead of print Maier AK. Eye 2014 Nov 21 epub ahead of print Hwang/UCSF Hwang/UCSF 8
Advantages My EK Algorithm • DMEK ideal for UT-DSAEK DMEK Fuchs dystrophy or mod. corneal edema Donor preparation Speed of visual recovery Uncomplicated anatomy Graft deployment Endothelial cell loss Visual potential of 20/20 Rebubble rate Primary graft failure Preop vision 20/60 or better Learning curve Allograft rejection rate Patient satisfaction Hwang/UCSF Hwang/UCSF My EK Algorithm My EK Algorithm • Ultrathin DSAEK ideal for • Reserve PK for Severe corneal edema Concurrent stromal scarring Tubes, iris defects, absent post. capsule Need for combined vitreoretinal surgery Status post vitrectomy Flat or absent anterior chamber Visual potential of 20/25 or worse requiring open sky reconstruction Preop vision 20/70 - CF Inability to comply with postop positioning Visual potential of 20/200 or worse Preop vision HM - LP Hwang/UCSF Hwang/UCSF 9
Medical Therapy for Fuchs? DSAEK vs. DMEK • 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 DSAEK DMEK 20/25- 20/20- 2009 2014 Hwang/UCSF Hwang/UCSF Rho-Kinase Inhibitors in Fuchs Rho-Kinase Inhibitors in Fuchs Koizumi N. Cornea 2013;32:1167-70 Hwang/UCSF Koizumi N. Cornea 2013;32:1167-70 Hwang/UCSF 10
Rho-Kinase Inhibitors in Fuchs 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 Koizumi N. Cornea 2013;32:1167-70 Hwang/UCSF Hwang/UCSF Questions? Thank You david.hwang@ucsf.edu Hwang/UCSF Hwang/UCSF 11
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