Carelli mitocon 2012

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Carelli mitocon 2012

  1. 1. Opzioni terapeutiche nelleneuropatie ottiche mitocondriali Valerio Carelli Laboratorio di Neurogenetica, IRCCS Istituto delle Scienze Neurologiche di Bologna Dipartimento di Scienze Neurologiche, Università di Bologna
  2. 2. Leber’s Hereditary Optic Neuropathy (LHON) maternally inherited: over 90% of cases carry a inheritedmtDNA point mutation affecting complex I at nps11778/ND4 (Wallace et al. 1988), 3460/ND1, and 3460/ND114484/ND6 male prevalence variable penetrance despite most LHON maternallineages are homoplasmic mutant acute/subacute central vision loss (papillomacularbundle) in young/adults retinal ganglion cell death (tissue specificity)
  3. 3. Dominant Optic Atrophy (DOA) mendelian inheritance (autosomal dominant): mostpatients are linked to loss-of-function mutations affectingthe OPA1 gene (Delettre et al. 2000; Alexander et al.2000), which encodes a protein targeted tomitochondria. This protein is a dynamin-relatedGTPase involved in formation and maintenance ofmitochondrial network and morphology variable penetrance slowly progressive loss of central vision(papillomacular bundle) with onset before age 10 retinal ganglion cell death (tissue specificity)
  4. 4. Natural history of Leber’s hereditary optic neuropathy
  5. 5. Natural history of Leber’s hereditary optic neuropathy: optical coherence tomography correlated pattern
  6. 6. NATURAL HISTORY OF LHONBarboni et al., Ophthalmology 2010
  7. 7. A specific pattern of neurodegeneration
  8. 8. THERAPY FOR LHON• Idebenone and EPI-743• Activation of mitochondrial biogenesis for carriers• Anti-apoptotic drugs for acute phase• Gene therapy: allotopic expression• Gene therapy: xenotopic expression of alternative oxidase (S. Cervisiae single subunit NADH oxidase Ndi1)
  9. 9. Therapy: idebenone, BRAIN 2011
  10. 10. 14484 patients do 11778 patients do betterbetter anyways after idebenone treatment
  11. 11. Idebenone in DOA patients
  12. 12. CONCLUSIONSIdebenone treated patients with the 11778/ND4 mutation had significantly increased rate of visual recovery compared to untreatedThe duration of therapy was longer for patients recovering vision and earlier start of therapy correlated with earlier onset of visual recovery “in-between eyes” idebenone treatment did not spare the second eye
  13. 13. EPI-743
  14. 14. LHON patients treated with EPI-743 at Doheny Eye Institute (courtesy Prof. Alfredo A. Sadun)Complete reversion Partial recovery Progression
  15. 15. Tre pazienti in trattamentso con EPI-743 in Italia• 300 mg x 3/die• Inclusione dei pz in stadio molto precoce della fase acuta monolaterale• Diagnosi genetica di mutazione classica (11778 o 3460)
  16. 16. PATIENT 1 – LHON/3460
  17. 17. PATIENT 2 – LHON/11778
  18. 18. Patient 3 – LHON/11778
  19. 19. Conclusions• 1 patient recovery• 1 patient unchanged natural history so far• 1 patient recovery plus second eye spared
  20. 20. Strategie per la LHON• Terapia con attivatori della biogenesi mitocondriale nei carriers di mutazione non affetti• Combinazione di farmaci antiapoptotici (ciclosporina etc..) e antiossidanti (idebenone e EPI-743) nella fase acuta• Antiossidanti (idebenone e EPI-743) e attivatori della biogenesi mitocondriale per i pz cronici
  21. 21. WHY RECOVERY OFVISUAL ACUITY??
  22. 22. REMYELINATION? MYELIN REMODELLING?
  23. 23. Myelin basic protein Neurofilaments MergeA B C 10 µmD E F 10 µm
  24. 24. Myelin basic protein Neurofilaments MergeA B C 10 µmD E F 10 µm
  25. 25. LHON/3460 – demyelinationA B
  26. 26. GRAZIE PER L’ATTENZIONE !
  27. 27. Unit of Neurogenetics:-Valerio Carelli, MD, PhD-Maria Lucia Valentino, MD-Chiara La Morgia, MD, PhD student-Sabrina Farne, lab technician’-Arianna Corbu, lab techincian-Luisa Iommarini, BiotechSc-Leonardo Caporali, BiotechSc-Alessandra Maresca, BiotechSc-Daniela Strobbe, BiotechSc

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