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EXONES
DNA
RNA
PROTEINA
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SMN 1SMN 2ADN
ARN mensajero
EXONES
PROTEINA SMN2 (sin exon 7)
inestable y parcialmente funcionante
PROTEINA SMN1 (completa)
totalmente funcionante
EX7
EX7
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SMN mRNA and protein in fetal SPINAL CORD
(15 weeks)
FL SMN (COMPLETE)
delta 7 SMN (INCOMPLETE)
Control SMA
Soler-Botija et al., JNEN, 2005
38kd
Ex7SMN1+SMN2 SMN2
SMN1+SMN2 SMN2
A decrease of SMN protein in spinal cord causes SMA
SMN transcripts
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PAUTAS MOTORAS EN LA AME
NUNCA SE SIENTAN NUNCA
CAMINAN PERDIDA DEAMBULACION
SMN 1
SMN 1SMN 2
SMN 2
SMN 2
SMN 2
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SMN 2
SMN 2
I SMN 2
Ningún paciente se ha descrito con ausencia de los dos genes SMN
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SMN 2
SMN 2
II / III
SMN 2
SMN 2
SMN 2 SMN 2
SMN 2
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TERAPIA FARMACOLOGICA
TERAPIA FARMACOLOGICA
???
Cambio RNA
Aumento proteína
completo
incompleto
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TERAPIA FARMACOLOGICA EN AME
Neuroprotección
Proteger y estimular músculo
¿Se pueden tratar los genes?
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Capping
SMN2 upregulation
Increasing RNA
VPA, Phenylbutyrate, Hydroxyurea, , Salbutamol
RG3039 (Repligen Corporation).
Including exon 7 in SMN2 transcripts.
Antisense oligonucleotides SMN RX (Isis)
SMN protein stabilizationReadthrough ALB-111NINDS)
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8U 76 876
Método para aumentar la inclusión del exon 7
2'-O-(2-methoxyethyl) ribose
phosphorothioate
5-methyl cytosine
G
OCH2CH2OCH3
O
A
OCH2CH2OCH3
O
T
OCH2CH2OCH3
O
C
OCH2CH2OCH3
O
PO
OOS
PO
OOS
PO
OOS
PO
OOS
O
868U 76R
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ISS-N1
GUAAGUCUGCCAGCAUUAUGAAAGUGAAUCUUACUUUUGUAAAACUUUAUGGUUUGUGGA …U1
ISE I7-1
A1/A2 A1/A2
ISIS-SMNRx (ASO-10-27)
Exon 7
ISIS-SMNRx: nuevo fármaco en investigación
ISIS-SMNRx
18mer; MW 7127Hua et al (2007) PLoS Biol 5: e73Hua et al (2008) Am J Hum Genet 82: 834Hua et al (2010) Genes Dev 24: 1634Passini et al (2011) Science Transl Med 3: 72ra18Hua et al (2011) Nature 478: 123 Dr. A. Krainer
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Intrathecal drug delivery
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Intrathecal drug delivery
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Transferir copias normales del gen SMN1 a la médula espinal (terapia génica).
– AAV9 que pasa la barrera hematoencefálica – Aumenta la supervivencia cuando se
administra muy precozmente al ratón SMA. – Se está estudiando en primates y hay un
protocolo para aprobación de la FDA
AAV9
SMN1
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Gene therapy of SMA mice with scAAV9-SMN
Foust et al., Nature
Biotechnology, 2010
14d 250d
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Rehabilitación FisioterapiaNutrición
RespiratorioCirugía
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Fármacología clásica aplicada a la base genética
Neuroprotectores
Mioprotectores
Terapia basada en RNA (incluir exon 7
en AME)
EL FUTURO: TERAPIA COMBINADA EN LA AME
¿TERAPIA CELULAR?¿TERAPIA GENICA
REEMPLAZO?
Rehabilitación FisioterapiaNutrición
RespiratorioCirugía
Concepto: es probable que no haya una sola solución terápéutica y se determinarán protocolos de tratamiento
Aumentar la expresión del gen SMN2 en AME
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Detener o retrasar el proceso
Mejorar la calidad de vida
Curación
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Protocolos sobre terapia en la AME
• Terapia central versus periférica
• Ventana terapéutica
• Tiempo y frecuencia de administración
• Combinación de terapias
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12
3 4
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Diaphragm 14 weeks Motor Endplates
NF+Syn AchR gamma
NF+Syn AchR gamma
AXONS - ENDPLATES
Martínez-Hernández et al. (J Pathol 2013)
CONTROL SMA
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Protocolos sobre terapia en la AME
• Eficacia terapéutica versus realidad biológica enfermedad
• Curación, detener el proceso, cambiar de tipo de AME
• Manifestaciones de la enfermedad con las nuevas terapias
• Trasfondo biosicosocial
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CONCEPTO DE DISCAPACIDAD NO COMO ENFERMEDAD SINO COMO QUE NACE DE LAS DIFICULTADES DEL MUNDO EXTERIOR E
INTERIOR
ORGANISMO
PSIQUISSOCIEDAD
MODELO BIOSICOSOCIAL
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8
8
Solo un pequeño cambio en la secuencia hace que el exon 7 se incluya menos
STOP
AAAA
GGT TTT AGA
STOP
AAAA7
GGT TTC AGA
SMN2
SMN1
76
6~100%
50 - 90%
10 - 50%
SMN
SMN∆7
TTC or TTT codify for PHENYLALANINE
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• Que sin proteína SMN no se puede vivir y que las demás células del organismo con poco se conforman, incluyendo las neuronas cerebrales pero no las neuronas motoras
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