Valrerio Carelli - Convegno Mitocon 2014
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  • 1. L’apparato visivo nei pazienti mitocondriali: le disfunzioni ed i trattamenti Valerio Carelli, MD, PhD IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy Neurology Unit, Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
  • 2. F V LUUR T P E LCUN SAGY H ND5 ND6 ND4 ND4L ND3 R COIII G ATPase6/8 KCOIID SUCN COI A N C Y W ND2 I M Q ND1 16S 12S D-loop Cyt.b D E L E T I O N S 3243A->G MELAS CPEO DDM tRNA-Ile mutations CARDIOPATHY 8344A->G MERRF tRNA-Ser mutations DEAFNESS 1555A->G DEAFNESS (aminoglycosides) cyt. b mutations MYOGLOBINURIC MYOPATHY 8993T->G NARP/MILS 3460G-A 11778G->A 14484T->C LHON PEO, KSS, Pearson
  • 3. Leber Hereditary Optic Neuropathy (mtDNA) Dominant optic atrophy (OPA1) Recessive optic atrophy X-linked optic atrophy
  • 4. Mito-pathways to RGCs loss OXPHOS deficiency (complex I) Reactive oxygen species (ROS) – calcium handling (mito-ER) Mito-dynamics-biogenesis-mitophagy Mitochondrial apoptosis
  • 5. NATURAL HISTORY OF LHON Barboni et al., Ophthalmology 2010
  • 6. A specific pattern of neurodegeneration
  • 7. The pattern of neuro-degeneration follows the axonal diameter starting from the smallest fibers on the temporal quadrant(papillo-macular bundle) The smallest fibers are the most vulnerable in maintaining the energy supply because their volume is limited in accommodating more mitochondria to compensate
  • 8. CONTROL LHON/3460
  • 9. A B C D E F Abnormal myelin maintenance 10 µm 10 µm A B C D E F
  • 10. A B What is the role of myelin maintenance in triggering RGCs loss or promoting RGCs sparing and function?
  • 11. -Axonal swelling, -Increase of abnormal mitochondria -Thinning of myelin -Preferential loss of smallest axons
  • 12. Mouse model of OPA1 haploinsufficiency (Prof. Luca Scorrano)
  • 13. COMMON THEMES LINKING RGC LOSS IN MITOCHONDRIAL OPTIC NEUROPATHIES mtDNA mutations: -OXPHOS (complex I) deficiency -increased ROS -mito-fragmentation -activated biogenesis/mitophagy -myelin pathology -vascular changes nDNA mutations: -OXPHOS (complex I/supercomplex) deficiency -increased ROS -mito-fragmentation -activated biogenesis/mitophagy -myelin pathology pathologic axonal transport and ultimately APOPTOSIS of RGCs
  • 14. Mitochondrial optic neuropathies are a convenient model for clinical trials: -only one tissue affected -fairly well understood pathogenesis and relatively predictable natural history -good quantitative outcome measures (visual acuity, visual fields, OCT assessments of retinal fiber layer thickness, etc.) -animal models available (OPA1 and ND6 mutants)
  • 15. THERAPY FOR LHON and DOA • Antioxidant - Idebenone and EPI-743 in affected • Activation of mitochondrial biogenesis for carriers • Anti-apoptotic drugs for acute phase • Gene therapy for LHON and NARP: allotopic expression • Gene therapy: xenotopic expression of alternative oxidase (S. Cervisiae single subunit NADH oxidase Ndi1) • Gene therapy for DOA: in haploinsufficiency, AAV- dependent delivery of OPA1
  • 16. Idebenone in LHON (and DOA) New LHON trial with idebenone in UK (Dr. Patrick Yu-Wai-Mann), with high dosages and for a longer time!
  • 17. EPI-743
  • 18. *Eye from this patient was excluded #Eye did not experience vision loss
  • 19. 0 50 100 150 200 AverageOCT RNFL 1 4 5 11 0 50 100 150 200 AverageOCT RNFL 2 3 6 9 13 15 0 50 100 150 200 0 6 12 18 24 AverageOCTRNFL Months of Treatment 7 8 9 14 -0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50 4,00 4,50 5,00 0 6 12 18 24 VisualAcuity(logMar) Months of Treatment 7 8 12 14 -0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50 4,00 4,50 5,00 VisualAcuity (logMar) 2 3 6 9 13 15 -0,50 0,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50 4,00 4,50 5,00 VisualAcuity (logMar) 1 4 5 11 -40 -30 -20 -10 0 MeanDeviation 2 3 6 9 13 15 -40 -30 -20 -10 0 MeanDeviation 1 4 5 11 -40 -30 -20 -10 0 0 6 12 18 24 MeanDeviation Months of Treatment 7 8 12 14 Figure 1. Mean deviation, logMar visual acuity and OCT average retinal nerve fiber layer from the 1st affected eye – from baseline to 24 months of EPI-743 therapy SignificantimprovementMildimprovementNoimprovement
  • 20. Figure 3. Examples of Humphrey visual fields at baseline and after 24 months of treatment Baseline 24 months after treatment A. C. E. B. D. F.
  • 21. Figure 4. Examples of color optic disc photographs at baseline and after 24 months of treatment. Baseline 24 months after treatment A. C. E. B. D. F.
  • 22. RNFL thickness between treated and untreated LHON patients Pretreatment 24-months18-months12-months EPI-743 Untreated affected LHON patients 97.8 64.3 65.0 67.8 50.4 Not statistically significant
  • 23. 0 20 40 60 80 100 120 140 Marked improvement Mild improvement No improvement OCTAverageRNFL 1st eye Baseline 24 months after treatment RNFL swelling as a negative prognostic marker for LHON patients on therapy *Definition of baseline: 6 months from vision loss The greater the initial RNFL swelling, the worse the final outcome for the 1st eye after 24 months with EPI-743 treatment
  • 24. THERAPY FOR LHON and DOA • Antioxidant - Idebenone and EPI-743 in affected • Activation of mitochondrial biogenesis for carriers • Anti-apoptotic drugs for acute phase • Gene therapy for LHON and NARP: allotopic expression • Gene therapy: xenotopic expression of alternative oxidase (S. Cervisiae single subunit NADH oxidase Ndi1) • Gene therapy for DOA: in haploinsufficiency, AAV- dependent delivery of OPA1
  • 25. Females are partially protected in LHON
  • 26. Oestrogens activate mito-biogenesis
  • 27. Conclusions Oestrogens present a multilayer effect on complex I defective LHON cybrids, leading to: -reduced ROS production -small but significant improvement in cybrids energetic competence -partial rescue of cell viability in galactose medium by restoring membrane potential and limiting apoptotic cell death -coordinated activation of mitochondrial biogenesis
  • 28. THERAPY FOR LHON and DOA • Antioxidant - Idebenone and EPI-743 in affected • Activation of mitochondrial biogenesis for carriers • Anti-apoptotic drugs for acute phase • Gene therapy for LHON and NARP: allotopic expression • Gene therapy: xenotopic expression of alternative oxidase (S. Cervisiae single subunit NADH oxidase Ndi1) • Gene therapy for DOA: in haploinsufficiency, AAV- dependent delivery of OPA1
  • 29. Dubbi sull’efficienza della metodica
  • 30. Ancora risultati controversi
  • 31. • We took advantage of cell models harboring the homoplasmic disruptive m.3571insC MTND1 mutation. We thereby demonstrated that allotopic expression of corrected mtDNA-encoded ND1 subunit complements and allows reassembly of human respiratory complex I along with recovery of bioenergetic deficiency, hence providing definitive proof that the allotopic expression is a feasible approach for gene therapy of mitochondrial diseases.
  • 32. Strategie per la LHON • Terapia preventiva in fase pre-sintomatica: attivatori della biogenesi mitocondriale nei carriers di mutazione non affetti e terapia genica • Terapia in fase acuta: combinazione di farmaci antiapoptotici (ciclosporina etc..?) e antiossidanti (idebenone e EPI-743) o terapia genica • Terapia in fase cronica: antiossidanti (idebenone e EPI-743) e attivatori della biogenesi mitocondriale e/o terapia genica
  • 33. Thanks for the attention and thanks to the many collaborators: • Alfredo A. Sadun, USC, Los Angeles • Rubens Belfort Jr, UNIFESP, Sao Paolo • Carla Giordano, University “La Sapienza”, Rome • Palmiro Cantatore, University of Bari, Bari • Anna Ghelli, University of Bologna, Bologna • Pio D’Adamo, University of Trieste, Trieste • Vamsi Mootha, Harvard, Boston • Massimo Zeviani, MRC, Cambridge • Patrick Chinnery and Patrick Yu-Wai-Man, University of Newcastle, Newcastle • Piero Barboni, San Raffaele, Milano • Lab of Neurogenetics: Alessandra Maresca, Leonardo Caporali, Sabrina Farne’, Chiara La Morgia, Maria Lucia Valentino
  • 34. Melanopsin expressing retinal ganglion cells (mRGCs) survive in LHON and DOA
  • 35. Melanopsin RGCs and conventional RGCs are loaded with mitochondria mRGC mRGC RGC RGC RGC RGC Courtesy Fred Ross Cisneros and Carla Giordano