How far away is spinal muscular atrophy gene therapy?

Gillingwater, Thomas H.; Murray, Lyndsay M.

doi:10.1586/14737175.2015.1070672

Cited by 3 publications

(5 citation statements)

References 17 publications

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“…Gene‐specific and mutation‐specific therapies are under development, and patients who know their genetic profile will be able to judge their suitability for clinical trials. Other compelling reasons may drive the desire for testing, including ascertaining the susceptibility of family members, facilitating reproductive decisions, guiding life planning (e.g., choosing a career that does not involve vigorous physical activity, retiring early, or moving to a handicapped‐accessible home), or identifying specific variants, such as the A4V SOD1 mutation in ALS, which are known to be associated with a distinct prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…Portable usage rights Genetic material may be stored in repositories and used for applications far removed from the original indication, such as research Information about susceptibility to other disorders Results may identify conditions that are unexpected based on personal or family history Uncertain impact on risk for disease Not all carriers of mutations will develop the disease, age of onset will vary, and severity will differ Reinterpretation and change in relevance over time Knowledge of genetic variants and their significance is evolving rapidly Privacy concerns Individuals whose samples are supposedly de-identified may be identified later by genomic analysis alone Relevance to family members Affects relatives' susceptibility to the disease Reproductive decision-making Information may impact decisions to have children information will empower them to make better treatment decisions. 12 Gene-specific and mutation-specific therapies are under development, 13,14 and patients who know their genetic profile will be able to judge their suitability for clinical trials. Other compelling reasons may drive the desire for testing, including ascertaining the susceptibility of family members, facilitating reproductive decisions, guiding life planning (e.g., choosing a career that does not involve vigorous physical activity, retiring early, or moving to a handicapped-accessible home), or identifying specific variants, such as the A4V SOD1 mutation in ALS, 15 which are known to be associated with a distinct prognosis.…”

Section: Informedmentioning

confidence: 99%

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Ethical issues in the evaluation of adults with suspected genetic neuromuscular disorders

Kang

Russell

et al. 2016

Muscle and Nerve

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Genetic testing is rapidly becoming an increasingly significant part of the diagnostic armamentarium of neuromuscular clinicians. Although technically easy to order, the results of such testing, whether positive or negative, have potentially enormous consequences for the individual tested and for family members. As a result, ethical considerations must be in the forefront of the physician's agenda when obtaining genetic testing. Informed consent is an important starting point for discussions between physicians and patients, but the counseling embedded in the informed consent process must be an ongoing part of subsequent interactions, including return of results and follow-up. Patient autonomy, including the right to know and right not-to-know results, must be respected. Considerations of capacity, physician beneficence and nonmaleficence, and privacy all play roles in the process. Muscle Nerve 54: 997-1006, 2016.

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Section: Discussionmentioning

confidence: 99%

Section: Informedmentioning

confidence: 99%

Ethical issues in the evaluation of adults with suspected genetic neuromuscular disorders

Kang

Russell

et al. 2016

Muscle and Nerve

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“…se podría identificar pacientes susceptibles de tratamiento con oligonucleótidos intratecales o terapia genética con vectores virales en etapa previa al compromiso respiratorio y conociendo el número de copias seleccionar mejores candidatos para las mismas terapias (6,8). Por el contrario, en otras culturas, creencias religiosas y legislaciones, los estudios genéticos antenatales, en etapas tempranas del embarazo, han definido algoritmos para consejería a los padres de prácticas abortivas, en aquellas situaciones que se estima una alta posibilidad de una presentación clínica temprana (AME tipo 1) (9).…”

Section: Abreviaturasunclassified

“…Pese al impacto favorable de estas prácticas, esperable en la calidad de vida relacionada a salud (CVRS) del paciente y su familia, las cargas sicológicas, sociales y financieras constituyen procesos que requieren evaluaciones en el dominio de la bioética, especialmente desde la perspectiva moral de las familias y en la dimensión vivencial de lo que realmente significa criar, educar y rehabilitar a un niño(a) con discapacidad, cuando aquello trastoca la estructura y funcionalidad del modelo familiar, aún más en aquellos con ventilación mecánica prolongada (4,5). Actualmente en enfermedades genéticas, como es el caso de la atrofia muscular espinal (AME) (6), existe el desarrollo científico para conocer las mutaciones genéticas específicas y la expresión de genes reguladores que modifican la presentación fenotípica de la enfermedad y por ende las posibilidades de un mayor compromiso muscular, incluida la falla ventilatoria (7).…”

Section: Introductionunclassified

“…Del mismo modo las posibilidades de tratamientos etiológicos de base genético, sistémico e intratecal, que modifican estas expresiones fenotípicas, se están desarrollando por medio de estudios clínicos en pacientes con AME tipo 1 y 2 (6)(7)(8). Ambas perspectivas abren nuevos desafíos técnicos, pero fundamentalmente éticos, al surgir la posibilidad de tamizaje neonatal y antenatal para estudio de deleciones en el gen de supervivencia de motoneuranas (SMN) tipo 1, como en el número de copias del gen regulador SMN tipo 2.…”

Section: Introductionunclassified

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Cuidados Respiratorios Para Pacientes Con Enfermedades Neuromusculares

Salinas¹,

Prado²,

Pinchak³

et al. 2017

Neumol Pediatr

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Los cuidados respiratorios no invasivos, combinando la asistencia ventilatoria, inicialmente nocturna y luego durante las 24 h del día, incluso en pacientes con capacidad vital mínima, más la implementación de estrategias complementarias de tos asistida, respiración glosofaríngea y apilamiento de aire (air stacking) en forma activa o pasiva han contribuido a una mejor calidad de vida y sobrevida de los pacientes con enfermedades neuromusculares. Resulta esencial que los profesionales de la salud, conozcan todas las opciones terapéuticas al informar a sus pacientes y sus familias, de modo que ellos puedan tomar sus mejores decisiones en la medida que la debilidad e hipoventilación progresen. Los avances tecnológicos, la capacitación de los pacientes y sus cuidadores facilitan su estadía en el hogar sin depender de instituciones o cuidados de enfermería permanentes, promoviendo su autonomía e integración, disminuyendo el riesgo de falla respiratoria conducente a intubación endotraqueal y/o a traqueostomia. Los días 24 y 25 de noviembre del 2016, en Montevideo tuvo lugar un encuentro de capacitación en cuidados respiratorios no invasivos con más de 200 profesionales médicos, kinesiólogos y licenciadas de enfermería, destacando los avances y experiencia consolidad por el Dr. John Bach en más de 30 años de ejercicio profesional en pacientes con síndromes de hipoventilación secundario a enfermedades neuromusculares y otras condiciones que debilitan la bomba respiratoria. Las recomendaciones claves se resumen en este articulo, destacando como estos avances requieren impulsar un cambio de paradigma en la forma en que los profesionales de la salud ven y tratan a estos individuos.

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Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice

Kim

Caine

Awano

et al. 2017

Human Molecular Genetics

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Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy.

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How far away is spinal muscular atrophy gene therapy?

Cited by 3 publications

References 17 publications

Ethical issues in the evaluation of adults with suspected genetic neuromuscular disorders

Ethical issues in the evaluation of adults with suspected genetic neuromuscular disorders

Cuidados Respiratorios Para Pacientes Con Enfermedades Neuromusculares

Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice

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