mitocon 2012

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

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

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)

Natural history of Leber’s hereditary optic neuropathyNatural history of Leber’s hereditary optic neuropathy

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

NATURAL HISTORY OF LHONNATURAL HISTORY OF LHONBarboni et al., Ophthalmology 2010

A specific pattern of neurodegenerationA specific pattern of neurodegeneration

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)

Therapy: idebenone, BRAIN 2011Therapy: idebenone, BRAIN 2011

14484 patients do 14484 patients do better anywaysbetter anyways

11778 patients do better 11778 patients do better after idebenone treatmentafter idebenone treatment

Idebenone in DOA patientsIdebenone in DOA patients

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

EPI-743 EPI-743

Complete reversion Partial recovery Progression

LHON patients treated with EPI-743 at Doheny Eye Institute (courtesy Prof. Alfredo A. Sadun)

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)

PATIENT 1 – LHON/3460PATIENT 1 – LHON/3460

PATIENT 2 – LHON/11778PATIENT 2 – LHON/11778

Patient 3 – LHON/11778Patient 3 – LHON/11778

ConclusionsConclusions

• 1 patient recovery

• 1 patient unchanged natural history so far

• 1 patient recovery plus second eye spared

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

WHY RECOVERY OF WHY RECOVERY OF VISUAL ACUITY??VISUAL ACUITY??

REMYELINATION?REMYELINATION?MYELIN MYELIN

REMODELLING?REMODELLING?

10 µm

10 µm

A B C

D E F

Myelin basic protein Neurofilaments Merge

10 µm

10 µm

A B C

D E F

Myelin basic protein Neurofilaments Merge

A B

LHON/3460 – demyelinationLHON/3460 – demyelination

GRAZIE PER L’ATTENZIONE !GRAZIE PER L’ATTENZIONE !

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