carelli mitocon 2012
TRANSCRIPT
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Opzioni terapeutiche nelle Opzioni terapeutiche nelle neuropatie ottiche mitocondrialineuropatie ottiche mitocondriali
Valerio Carelli
Laboratorio di Neurogenetica,IRCCS Istituto delle Scienze Neurologiche di Bologna
Dipartimento di Scienze Neurologiche,Università di Bologna
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maternally inheritedmaternally inherited: over 90% of cases carry a mtDNA point mutation affecting complex I at nps 11778/ND411778/ND4 (Wallace et al. 1988), 3460/ND13460/ND1, and 14484/ND6 14484/ND6
Leber’s Hereditary Optic Leber’s Hereditary Optic Neuropathy (LHON)Neuropathy (LHON)
acute/subacute central vision loss (papillomacular bundle) in young/adultsin young/adults retinal ganglion cell death (tissue specificity)
male prevalencemale prevalence
variable penetrancevariable penetrance despite most LHON maternal lineages are homoplasmic mutant
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mendelian inheritance (autosomal dominant):mendelian inheritance (autosomal dominant): most patients are linked to loss-of-function mutations affecting the OPA1 geneOPA1 gene (Delettre et al. 2000; Alexander et al. 2000), which encodes a protein targeted to mitochondria. This protein is a dynamin-related dynamin-related GTPaseGTPase involved in formation and maintenance of mitochondrial network and morphology variable penetrancevariable penetrance
Dominant Optic Atrophy Dominant Optic Atrophy (DOA)(DOA)
slowly progressive loss of central visioncentral vision (papillomacular bundle) with onset before age 10 retinal ganglion cell death (tissue specificity)retinal ganglion cell death (tissue specificity)
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Natural history of Leber’s hereditary optic neuropathyNatural history of Leber’s hereditary optic neuropathy
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Natural history of Leber’s hereditary optic neuropathy:Natural history of Leber’s hereditary optic neuropathy:optical coherence tomography correlated patternoptical coherence tomography correlated pattern
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NATURAL HISTORY OF LHONNATURAL HISTORY OF LHONBarboni et al., Ophthalmology 2010
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A specific pattern of neurodegenerationA specific pattern of neurodegeneration
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THERAPY FOR LHONTHERAPY FOR LHON
• Idebenone and EPI-743Idebenone 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)
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Therapy: idebenone, BRAIN 2011Therapy: idebenone, BRAIN 2011
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14484 patients do 14484 patients do better anywaysbetter anyways
11778 patients do better 11778 patients do better after idebenone treatmentafter idebenone treatment
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Idebenone in DOA patientsIdebenone in DOA patients
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CONCLUSIONSCONCLUSIONSIdebenone 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
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EPI-743 EPI-743
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Complete reversion Partial recovery Progression
LHON patients treated with EPI-743 at Doheny Eye Institute (courtesy Prof. Alfredo A. Sadun)
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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)
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PATIENT 1 – LHON/3460PATIENT 1 – LHON/3460
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PATIENT 2 – LHON/11778PATIENT 2 – LHON/11778
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Patient 3 – LHON/11778Patient 3 – LHON/11778
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ConclusionsConclusions
• 1 patient recovery
• 1 patient unchanged natural history so far
• 1 patient recovery plus second eye spared
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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
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WHY RECOVERY OF WHY RECOVERY OF VISUAL ACUITY??VISUAL ACUITY??
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REMYELINATION?REMYELINATION?MYELIN MYELIN
REMODELLING?REMODELLING?
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10 µm
10 µm
A B C
D E F
Myelin basic protein Neurofilaments Merge
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10 µm
10 µm
A B C
D E F
Myelin basic protein Neurofilaments Merge
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A B
LHON/3460 – demyelinationLHON/3460 – demyelination
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GRAZIE PER L’ATTENZIONE !GRAZIE PER L’ATTENZIONE !
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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