Farmaci modulatori dei processi di fu sione e fissione

Alcuni composti sperimentali, quali l’inibitore di DRP1 MDIVI-1 e l’idra- zone M1 che si ritiene promuova la fusione mitocondriale agendo su MNF o OPA1, sono in grado di interferire con i processi di fissione-fu- sione, ma il potenziale terapeutico di questi composti deve comunque essere ancora verificato. Tuttavia, i cosiddetti peptidi di Szeto-Schiller (SS) sono stati utilizzati per correggere i difetti dell’ultrastruttura mito- condriale in varie condizioni, quali l’atrofia muscolare, l’insufficienza car- diaca, l’ischemia-riperfusione ed il diabete. I peptidi SS sono tripeptidi in grado di penetrare nella cellula e di accumularsi nei mitocondri dove legano la cardiolipina, un componente lipidico della membrana mitocon- driale interna con attività di modulazione della catena respiratoria e di strutturazione delle creste. Inoltre, la cardiolipina modula l’attività di OPA1, ed è possibile che questo possa spiegare almeno in parte gli effetti dei peptidi SS sulla struttura delle creste.125

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4.Conclusioni

Benché negli ultimi 20 anni si sia assistito ad un impressionante au- mento delle nostre conoscenze sui meccanismi genetici e biochimici alla base della SLA, lo sviluppo di approcci terapeutici in grado di mi- gliorare in modo significativo il decorso clinico non è stato altrettanto soddisfacente. Al momento, la terapia della SLA rimane basata su inter- venti supportivi, mirati ad affrontare le complicanze della malattia. Tut- tavia negli ultimi anni sono emerse nuove strategie terapeutiche, la cui efficacia è stata dimostrata almeno a livello preclinico. Molti dei farmaci in via di studio sono attualmente considerati dei potenziali agenti tera- peutici per la SLA. Comunque, raramente è stato possibile replicare nei pazienti gli effetti ottenuti nei modelli animali di SLA. Tali fallimenti po- trebbero ammettere varie spiegazioni:

➢ molti farmaci non riescono ad attraversare la barriera ematoence- falica in maniera efficace;

➢ risultati promettenti sono spesso ottenuti dai farmaci somministrati nella fase presintomatica della malattia (nei modelli animali); ➢ poiché la popolazione dei pazienti con la SLA è piccola e la pato-

genesi è in parte sconosciuta, gli effetti clinici sono considerati come unico punto finale nei trial clinici randomizzati.

Tuttavia, una maggior collaborazione tra aziende farmaceutiche, ricer- catori di base, ricercatori clinici e neurologi renderà possibile lo sviluppo di una terapia efficace contro la SLA. Il più grande successo terapeutico probabilmente sarà ottenuto mediante l’utilizzo di un singolo farmaco, capace di agire su più fronti oppure dalla combinazione di più farmaci con meccanismi d’azione diversi. 114,123

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