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Amaurosis congénita de Leber : Luxturna - Leber congenital amaurosis : Luxturna

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Terapia Genica para amaurosis congenita de Leber: Luxturna (voretigene neparvovec-rzyl) -
Gene therapy for Leber congenital amaurosis: Luxturna (voretigene neparvovec-rzyl)

Publicado en: Salud y medicina
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Amaurosis congénita de Leber : Luxturna - Leber congenital amaurosis : Luxturna

  1. 1. Amaurosis congénita de Leber (ACL) Diego A. Valera Cornejo Servicio de Retina y Vítreo
  2. 2. Amaurosis congénita de Leber (ACL) • Descrita en 1869 por Theodore Leber. • 2° causa mas frecuente luego de retinosis pigmentosa. ( 5% de todas las distrofias) • Grupo de distrofias de la retina inicio en la infancia ( 6 meses) temprana, graves y de herencia autosómica recesiva • Evidente en los primeros meses de vida con nistagmo, respuestas pupilares ausentes y un electroretinograma no detectable. • Prevalencia de 1 en 33,000 a 1 per 81,000. • Alcanza el 20% de ceguera legal en niños. Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis. Proc Natl Acad Sci USA 1998; 95: 3088–93.
  3. 3. Fenotipo muy variable • Primeros 6 años disminución de agudeza visual, nistagmus • Fenotipo varía de acuerdo a gen afectado • Mutaciones CRB1, LRAT, CEP290, or RPE65 agudeza visual >20/50 y tienen manifestaciones en edades tempranas, – Distrofias retinianas de la infancia de presentación temprana (EOSRD) – Distrofias retinianas de presentación temprana severas ( SECORD) • La visión disminuye progresivamente en todos los pacientes • Fenotipo muy variable que incluye a veces fondo de ojo normal. Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber’s congenital amaurosis. Age-related findings in 35 patients. Ophthalmology. 1992; 99:241-245 MUTACION EN GUCY2DMUTACION EN RPE 65MUTACION EN CEP 920 MUTACION EN RDH 12
  4. 4. Genes identificados para LCA
  5. 5. Heterogeneidad genética: 25 genes asociados a la enfermedad Kumaran N, et al. Br J Ophtalmol. 2017 Sep; 101(9):1147-1154
  6. 6. Diagnóstico clínico inicial en pacientes con mutación bi alelica de RPE 65
  7. 7. Mutaciones bialelicas en RPE 65 • Amaurosis congénita de Leber tipo 2 • Retinosis pigmentosa Tipo 20 • Distrofias de inicio temprano • Distrofias severas mediadas por bastones • Eventualmente llevan a ceguera.
  8. 8. Terapia génica para ACL por mutaciones en RPE65 Inyección subrretiniana de virus adeno-asociado (AAV) serotipos 2 y 4 con expresión de RPE65 normal a perros RPE65 -/-. Recuperaron función de bastones y movilidad en luz tenue. 2001
  9. 9. Terapia génica para ACL por mutaciones en RPE65 2008
  10. 10. Terapia génica para ACL por mutaciones en RPE65 2018
  11. 11. LUXTURNA – TERAPIA GENICA PARA ENFERMEDADES RELACIONADAS A MUTACIONES DE RPE65
  12. 12. Diciembre 2017 Agosto 2018
  13. 13. Diciembre 2017 Agosto 2018
  14. 14. Criterios de inclusión • Pacientes mayores de 3 años • Enfermedad genética MUTACIÓN BIALELICA DEL RPE 65 • Vision menor de 20/60 • Grosor macular de mas de 100 um • Evaluación de movilidad multiluminancia – Multi-luminance mobility test (MLMT)
  15. 15. Voretigene neparvovec (AAV2-hRPE65v2) • Es un virus recombinante adeno-asociado de serotipo 2 (AAV2) • Promotor de citomegalovirus (CMV) • Promotor de beta actina de pollo (CβA) que dirige la expresión del gen del epitelio pigmentario de la retina humano 65 kDa de proteína (hRPE65)
  16. 16. Protocolo Inyección de 1·5 × 10¹¹ vg voretigene neparvovec en un total de volumen sub retinal de 0·3 mL --- 2 a 3 semanas luego , el ojo contralateral era inyectado
  17. 17. Evaluación de movilidad multiluminancia Multi-luminance mobility test (MLMT)
  18. 18. Evaluación de movilidad multiluminancia Multi-luminance mobility test (MLMT)
  19. 19. Evaluación de movilidad multiluminancia ( MLMT) a 1 año
  20. 20. Evaluación de movilidad multiluminancia ( MLMT) a 1 año 89% pacientes 65% pacientes Nivel mas bajo de oscuridad
  21. 21. Evaluación de movilidad multiluminancia ( MLMT) a 3 años
  22. 22. • https://luxturna.com/about-luxturna/#what- were-the-results
  23. 23. Visión a ( Ganancia de letras) 1 año
  24. 24. Visión a 3 años ( BCVA Log mar)
  25. 25. Resultados secundarios ( campo visual)
  26. 26. Campo visuales al año 2
  27. 27. Campo visual a 3 años
  28. 28. Fase I Resonancia Magnética Activación de corteza
  29. 29. Efectos Adversos
  30. 30. PRECIO - Tratamiento completo (> 1 000 000 USD)
  31. 31. dentifier Sponsor Target Gene Agent Delivery Phase Status NCT00516477 Safety Study in Subjects With Leber Congenital Amaurosis Spark Therapeutics RPE65 AAV2-hRPE65v2 Subretinal I Ongoing NCT02781480 Clinical Trial of Gene Therapy for the Treatment of Leber Congenital Amaurosis (LCA) (OPTIRPE65) MeiraGTx UK II Ltd RPE65 AAV2/5 OPTIRPE65 Subretinal I Ongoing NCT00481546 Phase I Trial of Gene Vector to Patients With Retinal Disease Due to RPE65 Mutations (LCA) University of Pennsylvania RPE65 rAAV2-CBSB-hRPE65 Subretinal I Ongoing NCT02946879 Long-Term Follow-Up Gene Therapy Study for Leber Congenital Amaurosis OPTIRPE65 (Retinal Dystrophy Associated With Defects in RPE65) MeiraGTx UK II Ltd RPE65 AAV2/5-OPTIRPE65 Subretinal I and II Ongoing NCT00749957 Phase 1/2 Safety and Efficacy Study of AAV- RPE65 Vector to Treat Leber Congenital Amaurosis Applied Genetic Technologies Corp RPE65 rAAV2-CB-hRPE65 Subretinal I and II Ongoing NCT01208389 Phase 1 Follow-on Study of AAV2-hRPE65v2 Vector in Subjects With Leber Congenital Amaurosis (LCA) 2 Spark Therapeutics RPE65 AAV2-hRPE65v2 Subretinal I and II Ongoing NCT00643747 Safety Study of RPE65 Gene Therapy to Treat Leber Congenital Amaurosis University College, London RPE65 tgAAG76 (rAAV 2/2.hRPE65p.hRPE65) Subretinal I and II Completed NCT01496040 Clinical Gene Therapy Protocol for the Treatment of Retinal Dystrophy Caused by Defects in RPE65 (RPE65) Nantes University Hospital RPE65 rAAV2/4.hRPE65 Subretinal I and II Completed NCT00999609 Safety Study in Subjects With Leber Congenital Amaurosis Spark Therapeutics RPE65 AAV2-hRPE65v2 Subretinal III Ongoing NCT03140969 Study to Evaluate QR-110 in Subjects With Leber's Congenital Amaurosis (LCA) Due to the c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene ProQR Therapeutics CEP290 QR-110 Intravitreal I and II Approved, not yet started NCT01521793 Repeated Treatments of QLT091001 in Subjects With Leber Congenital Amaurosis or Retinitis Pigmentosa (Extension of Study RET IRD 01) QLT Inc. RPE65, LRAT QLT091001 Oral I Completed NCT01014052 Safety/Proof of Concept Study of Oral QLT091001 in Subjects With Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) Due to Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) Mutations QLT Inc. RPE65, LRAT QLT091001 Oral I Completed Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J. Med. 2015; 372:1920–1926.
  32. 32. Gracias

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