Terapija spinalne mišićne atrofije

master's thesis

• Title (english): Therapy of spinal muscular atrophy
• Author: Diana Stipić
• Mentor: Nina Barišić (mentor)
• Committee member: Mario Ćuk (predsjednik povjerenstva)
• Committee member: Marija Jelušić (član povjerenstva)
• Committee member: Nina Barišić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Pediatrics); Zagreb
• Defense date and country: 2018-07-13, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Neurology
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Pediatrics

Abstract

Spinalna mišićna atrofija (SMA) je autosomno recesivna neurodegenerativna bolest, koju karakterizira gubitak funkcije gena SMN1 i smanjena razina SMN proteina. Dijeli se na 5 tipova (0-IV), koji se prezentiraju rasponom kliničke slike od progresivne mišićne slabosti i prerane smrti (tip 0) sve do blagog gubitka motoričkih neurona i normalnog očekivanog životnog vijeka (tip IV). Bez obzira ne heterogenu kliničku sliku najčešći je genetski uzrok dojenačke smrti. U zadnjih nekoliko godina, istraživanja terapije SMA su iznimno napredovala zbog boljeg razumijevanja molekularne podloge SMA, patogeneze i prirodnog tijeka bolesti. Glavna 4 terapijska pristupa obuhvaćaju zamjenu gena SMN1, povećanje transkripcije gena SMN2 u funkcionalni SMN protein, neuroprotekciju i povećanje mišićne snage i funkcije. Prvi lijek odobren kao terapija SMA je nusinersen (Spinraza), protusmjerni oligonukleotid, koji se daje intratekalno i djeluje modificirajući splicing pre-mRNA gena SMN2 i tako povećava stvaranje funkcionalnog SMN proteina. Odobren je za sve tipove SMA, ali s boljim odgovorom pri ranijem davanju terapije, što ukazuje na potrebu uvođenja novorođenačkog genetskog probira. Nusinersen ne dovodi do izliječenja, ali se još iščekuju rezultati produljenih kliničkih istraživanja. Kod ostalih potencijalnih lijekova također se čekaju rezultati istraživanja, koji su do sada bili obećavajući. Trenutačno je najbitniji multidisciplinarni klinički pristup, kojim se utječe na prirodni tijek bolesti i poboljšava kvaliteta života.

Abstract (english)

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by loss of function of SMN1 gene, and a reduced amount of the survival motor neuron (SMN) protein. The disease is categorized into five types (0-IV), with the clinical appearance ranging from progressive muscular weakness and premature death (type 0) to limited motor neuron loss and normal life expectancy (type IV). Although SMA is clinically heterogeneous, it is still the most frequent genetic cause of death in infants. Over the last years, research into treatments for spinal muscular atrophy has progressed enormously because of improved understanding of the molecular basis of SMA, disease pathogenesis, and natural history. The main 4 therapeutic strategies include SMN1 gene replacement, increased transcription of SMN2 gene into a functioning SMN protein, neuroprotection, and improvement of muscle strenght and function. The first treatment to be registered for SMA was Nusinersen (Spinraza), an antisense oligonucleotide intrathecally administered drug that modifies pre-mRNA splicing of the SMN2 gene and thus promotes increased production of functioning SMN protein. It is approved for all types of SMA, but with a better response in early treatment, which points out the need to introduce newborn genetic screening. Nusinersen is not a cure therapy, but the results of extension clinical trials are still awaited. The research result of the other potential drugs are also being awaited, that were promising so far. At the moment, the multidisciplinary clinical approach is the most important, because it affects the natural history of the disease and improves the quality of life.

• Keywords: muskularna atrofija; spinalna; terapija; nusinersen; multidisciplinarni
• Keywords (english): muscular atrophy; spinal; therapy; Nusinersen; multidisciplinar
• Language: croatian
• URN:NBN: urn:nbn:hr:105:290473
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2019-01-03 09:17:05