Avanços terapêuticos na atrofia muscular espinhal ligada ao cromossomo 5q

Reed, Umbertina Conti; Zanoteli, Edmar

doi:10.1590/0004-282X20180011

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View and Review • Arq. Neuro-Psiquiatr. 76 (4) • Abr 2018 • https://doi.org/10.1590/0004-282X20180011 linkcopiar

Avanços terapêuticos na atrofia muscular espinhal ligada ao cromossomo 5q

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

A atrofia muscular espinhal (AME) é uma grave doença dos neurônios motores, de grande variabilidade clínica e causada na maioria dos casos por mutação em homozigose no gene SMN1. Pelo menos quatro fenótipos clínicos distintos são reconhecidos com base na idade de início e no grau de envolvimento motor. Tal variabilidade clínica é em parte relacionada com o número de cópias do gene SMN2. Até recentemente, apenas terapias de suporte estavam disponíveis. Atualmente, terapias especificas estão sendo desenvolvidas com base em diferentes mecanismos para aumentar o nível de proteína SMN; em particular oligonucleotídeos antissenso por via intratecal e inserção de cópia do gene SMN1, via endovenosa, usando vetor viral. Nesta revisão, objetivamos discutir as mais recentes e promissoras estratégias terapêuticas, com consideração especial aos aspectos patogênicos da doença e aos mecanismos de ação de tais terapias.

Palavras-chave:
atrofia muscular espinhal; doença do neurônio motor; oligonucleotídeos antissenso; terapia genética

Molecule / study	Target population /age / SMN2 copies	Sample size / study phase	Endpoints	Preliminary results
Nusinersen / ENDEAR³⁴	SMA1 / ≤ 6 months / 2 copies	121 infants / placebo-controlled / phase 3	HINE, CHOP-INTEND	51% of the patients had HINE improvement; major efficacy when illness duration < 12 weeks
Nusinersen / CHERISH³⁵	SMA2 and 3 / 2 to 12 years / 2 or 3 copies	126 patients / placebo-controlled / phase 3	HFMSE	57.3% of the patients had at least 3 points higher score in HFMSE
Nusinersen / NURTURE³⁶	Presymptomatic / 2 or 3 copies	20 infants / phase 2	HINE, WHO motor milestones	No patient died or needed ventilatory support, all achieved some of the expected HINE motor milestones for healthy infants based on age;
Nusinersen / SHINE, NCT02594124	SMA patients from other nusinersen studies	Open label / extension study		Ongoing
AVXS-101⁴²	SMA1 / < 6 months / 2 copies	15 infants / open label / phase 1-2	Safety and tolerability; death or permanent ventilation; ability to sit; CHOP-INTEND	Positive impact on the survival and on motor function; 11/12 patients achieved motor milestones not seen in this population; results depended on age at onset and basal motor function
AVXS-101 / STR1VE, NCT03306277	SMA 1 / < 6 months / 1 or 2 copies	Open label / phase 3	Achievement of independent sitting; event-free survival	Ongoing
RO7034067 / FIREFISH, NCT02913482	SMA1 / 1-7months / 2 copies	Open label / phase 2	Safety; sitting without support (BSID-III)	Ongoing
RO7034067 / SUNFISH, NCT02908685	SMA2 and 3 / 2 to 25 years	Placebo-controlled / phase 2	Safety; MFM-32	Ongoing
Branaplam / LMI070X2201, NCT02268552	SMA1 / 1-7 months	Phase 1/2		Ongoing
Olesoxime / TRO19622⁴⁴	SMA2 or 3 / 3 to 25 years	165 patients / controlled / Phase 2	MFM	Primary endpoint not met. Patients were stable compared to placebo.
Olesoxime / NCT02628743	SMA 2 or 3 / 3 to 25 years	Open label / Phase 2	MFM	Ongoing
CK-2127107 / NCT02644668	SMA 2 to 4 / > 12years	Placebo-controlled / phase 2	HFMS-E, 6MWT, FVC	Ongoing

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[TFN1] BSID-III: Bayley Scales of Infant and Toddler Development - third edition; CHOP-INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; FVC: forced vital capacity; HFMSE: Hammersmith Functional Motor Scale Expanded; HINE: Hammersmith Infant Neurological Examination; MFM: motor function measurement; SMA: spinal muscular atrophy; WHO: World Health Organization; 6MWT: six-minute walk test.