NOVÉ PERSPEKTIVY LÉČBY VROZENÝCH NERVOSVALOVÝCH ONEMOCNĚNÍ - SMA Doc. MUDr. Petr Vondráček, Ph.D. Klinika dětské neurologie, FN Brno

Příčina významné morbidity a mortality pediatrické populace Úvod Hereditární geneticky podmíněná nervosvalová onemocnění – medicínský a socioekonomický problém vyspělých zemí. Příčina významné morbidity a mortality pediatrické populace Prevalence 1:3500 (200 000 případů v EU) (3000 případů v ČR)

Historický přelom v možnostech léčby nervosvalových chorob? Úvod Spinální svalová atrofie (SMA I. A II. typu), M. Werdnig-Hoffmann), AR 5q13 2008 – 2012 Historický přelom v možnostech léčby nervosvalových chorob? Probíhající a plánována klinická hodnocení nových preparátů a terapeutických metod

Spinální svalová atrofie (SMA I. A II. typu), M Spinální svalová atrofie (SMA I. A II. typu), M. Werdnig-Hoffmann), AR 5q13, delece exonu 7 genu SMN1

fenylbutyrát sodný (PBA) kyselina suberoylanilid hydroxamová (SAHA) Perspektivy léčby SMA Ovlivnění exprese mRNA genu SMN2 inhibitory histonových deacetyláz – modifikací sestřihového vzorce Syntéza SMN proteinu fenylbutyrát sodný (PBA) valproát sodný (VPA) benzamid M344 kyselina suberoylanilid hydroxamová (SAHA)

fenylbutyrátu sodného (PBA) valproát sodný (VPA)

Další terapeutické možnosti salbutamol riluzol kmenové buňky

SMA - Aktuální klinické studie 1) Development of iPS From Donated Somatic Cells of Patients With Neurological Diseases This study is ongoing, but not recruiting participants. First Received: April 2, 2009   No Changes Posted Sponsored by: Hadassah Medical Organization Information provided by: Hadassah Medical Organization

This study has been terminated. 2) Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III (NPTUNE01) This study has been terminated. First Received: February 21, 2007   Last Updated: April 9, 2009   History of Changes Sponsors and Collaborators: Westat National Institute of Neurological Disorders and Stroke (NINDS) Information provided by: National Institute of Neurological Disorders and Stroke (NINDS)ClinicalTrials.gov Identifier: NCT00439569   Purpose The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; and to determine if the drug has an effect on SMN mRNA and protein levels.

This study has been completed. 3) Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy This study has been completed. First Received: September 23, 2005   Last Updated: December 23, 2007   History of Changes Sponsors and Collaborators: University of Utah Families of Spinal Muscular Atrophy Sigma Tau Pharmaceuticals, Inc. Abbott Information provided by: University of Utah

This study is currently recruiting participants. 4) CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I This study is currently recruiting participants. Verified by University of Utah, April 2009 First Received: April 14, 2008   Last Updated: April 24, 2009   History of Changes Sponsors and Collaborators: University of Utah Families of Spinal Muscular Atrophy Sigma Tau Pharmaceuticals, Inc. Information provided by: University of UtahClinicalTrials.gov Identifier: NCT00661453   Purpose This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.

This study is currently recruiting participants. 5) Valproic Acid in Ambulant Adults With Spinal Muscular Atrophy (VALIANT SMA) This study is currently recruiting participants. Verified by University of Utah, January 2009 First Received: May 30, 2007   Last Updated: January 13, 2009   History of Changes Sponsors and Collaborators: University of Utah Families of Spinal Muscular Atrophy Abbott Information provided by: University of UtahClinicalTrials.gov Identifier: NCT00481013   Purpose The primary objective of this proposal is to determine whether oral VPA is effective in treating SMA in adult patients.

This study is ongoing, but not recruiting participants. 6) Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I (NPTUNE02) This study is ongoing, but not recruiting participants. First Received: February 22, 2007   Last Updated: April 9, 2009   History of Changes Sponsors and Collaborators: Westat National Institute of Neurological Disorders and Stroke (NINDS) Information provided by: National Institute of Neurological Disorders and Stroke (NINDS)ClinicalTrials.gov Identifier: NCT00439218   Purpose The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy type I; and to determine if the drug has an effect on SMN mRNA and protein levels.

This study is currently recruiting participants. 7) Study to Evaluate Sodium Phenylbutyrate in Pre-Symptomatic Infants With Spinal Muscular Atrophy (STOP SMA) This study is currently recruiting participants. Verified by University of Utah, October 2008 First Received: September 10, 2007   Last Updated: October 9, 2008   History of Changes Sponsored by: University of Utah Information provided by: University of UtahClinicalTrials.gov Identifier: NCT00528268   Purpose In this single-center trial, we will evaluate the effects of NaPB on presymptomatic SMA type I (cohort 1)and presymptomatic SMA type II (cohort 2) infants. A variety of outcome measures will be performed at each study visit to follow the course of the disease. Total duration of the study for type I infants will be 18 months, for type II infants, 24 months.

8) Pilot Study of Growth Hormon to Treat SMA Typ II and III This study is ongoing, but not recruiting participants. First Received: September 12, 2007   Last Updated: November 5, 2008   History of Changes Sponsors and Collaborators: University Hospital Freiburg Novo Nordisk Information provided by: University Hospital FreiburgClinicalTrials.gov Identifier: NCT00533221   Purpose The purpose of this study is to determine whether Growth hormon can increase strength in spinal muscular atrophy type II and III.

This study is ongoing, but not recruiting participants. 9) A Pilot Therapeutic Trial Using Hydroxyurea in Type I Spinal Muscular Atrophy Patients This study is ongoing, but not recruiting participants. First Received: December 4, 2007   Last Updated: December 2, 2008   History of Changes Sponsored by: Stanford University Information provided by: Stanford UniversityClinicalTrials.gov Identifier: NCT00568698   Purpose The objectives of this trial are: to establish a safety profile for use of Hydroxyurea in children with Type I Spinal Muscular Atrophy; to identify reliable outcome measures for HU treatment in Type I SMA; and to detect the clinical efficacy of HU treatment in children with Type I SMA.

This study is ongoing, but not recruiting participants. 10) Study to Evaluate the Efficacy of Riluzole in Children and Young Adults With Spinal Muscular Atrophy (SMA) (ASIRI) This study is ongoing, but not recruiting participants. First Received: October 16, 2008   No Changes Posted Sponsored by: Assistance Publique - Hôpitaux de Paris Information provided by: Assistance Publique - Hôpitaux de ParisClinicalTrials.gov Identifier: NCT00774423   Purpose This is a multicentric, randomized, double-blind study versus placebo, with two parallel groups treated to evaluate the efficacy and the tolerance of Riluzole in children and young adults (6 to 20 years of age) with SMA. (Type II and Type III).

TREAT-NMD (Translational Research in Europe) Cíl projektu Vytvořit s pomocí moderních klinických, molekulárně genetických diagnostických metod a vyspělých informačních technologií racionální design budoucích terapeutických strategií, jako součást mezinárodních aktivit na tomto poli. Český SMA registr TREAT-NMD (Translational Research in Europe) http://www.treat-nmd.eu

Změny hladiny mRNA genu SMN2 o plné délce, mRNA genu SMN2 obsahující deleci exonu 7 a mRNA genu GAPDH v průběhu terapie VPA

Závěry Potvrdili jsme bezpečnost a nezávažné vedlejší účinky medikace PBA i VPA Zlepšení klinického stavu a motorických funkcí jsme prokázali u cca 40% pacientů se SMA léčených inhibitory histonových deacetyláz, kteří se jevili jako respondéři na léčbu těmito preparáty.

Závěry Praktický algoritmus sledování pacientů se SMA I. a II. typu na klinické a molekulárně biologické úrovni - vhodný pro budoucí rozsáhlejší kontrolované intervenční studie s dalšími inhibitory histonových deacetyláz.

TREAT-NMD: a network of excellence for neuromuscular diseases 2. dekáda 21. století – očekávána aplikace prvních terapeutických strategií závažných hereditárních nervosvalových onemocnění, zvláště SMA u pediatrických pacientů. TREAT-NMD: a network of excellence for neuromuscular diseases

Děkuji za pozornost Poděkování: RNDr. Lenka Fajkusová, CSc, CMBGT, IHOK, FN Brno Doc. MUDr. Markéta Hermanová, Ph.D., PAÚ FN Brno a FN u sv. Anny Ing. Petr Brabec, Institut biostatistiky a analýz, MU Prim. MUDr. Renata Gaillyová, OLG, FN Brno Doc. MUDr. Pavel Seeman, Ph.D., 2. LF UK Praha