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Terapia génica

La terapia genética es una tecnología médica que tiene como objetivo producir un efecto terapéutico a través de la manipulación de la expresión genética o mediante la alteración de las propiedades biológicas de las células vivas. [1] [2] [3]

El primer intento de modificar el ADN humano fue realizado en 1980, por Martin Cline , pero la primera transferencia genética nuclear exitosa en humanos, aprobada por los Institutos Nacionales de Salud , se realizó en mayo de 1989. [4] El primer uso terapéutico de la transferencia genética, así como la primera inserción directa de ADN humano en el genoma nuclear, fue realizado por French Anderson en un ensayo que comenzó en septiembre de 1990. Entre 1989 y diciembre de 2018, se realizaron más de 2900 ensayos clínicos, con más de la mitad de ellos en fase I. [ 5] En 2003, Gendicine se convirtió en la primera terapia genética en recibir aprobación regulatoria. Desde entonces, se aprobaron más fármacos de terapia génica, como alipogene tiparvovec (2012), Strimvelis (2016), tisagenlecleucel (2017), voretigene neparvovec (2017), patisiran (2018), onasemnogene abeparvovec (2019), idecabtagene vicleucel (2021), nadofaragene firadenovec , valoctocogene roxaparvovec y etranacogene dezaparvovec (todos en 2022). La mayoría de estos enfoques utilizan virus adenoasociados (AAV) y lentivirus para realizar inserciones genéticas, in vivo y ex vivo , respectivamente. Los AAV se caracterizan por estabilizar la cápside viral , menor inmunogenicidad, capacidad para transducir células en división y no división, el potencial para integrarse específicamente en el sitio y lograr una expresión a largo plazo en el tratamiento in vivo. [6] Los enfoques ASO / siRNA como los realizados por Alnylam e Ionis Pharmaceuticals requieren sistemas de administración no virales y utilizan mecanismos alternativos para el tráfico a las células hepáticas a través de transportadores GalNAc .

No todos los procedimientos médicos que introducen alteraciones en la composición genética de un paciente pueden considerarse terapia génica. Se ha descubierto que el trasplante de médula ósea y los trasplantes de órganos en general introducen ADN extraño en los pacientes. [7]

Fondo

La terapia génica se concibió por primera vez en la década de 1960, cuando se empezó a investigar la posibilidad de añadir nuevas funciones genéticas a las células de mamíferos . Se probaron varios métodos para hacerlo, incluida la inyección de genes con una micropipeta directamente en una célula viva de mamífero y la exposición de las células a un precipitado de ADN que contenía los genes deseados. Los científicos plantearon la teoría de que un virus también podría utilizarse como vehículo o vector para introducir nuevos genes en las células.

Una de las primeras científicas en informar sobre la incorporación directa exitosa de ADN funcional en una célula de mamífero fue la bioquímica Dra. Lorraine Marquardt Kraus (6 de septiembre de 1922 - 1 de julio de 2016) [8] en el Centro de Ciencias de la Salud de la Universidad de Tennessee en Memphis, Tennessee . En 1961, logró alterar genéticamente la hemoglobina de células de médula ósea tomadas de un paciente con anemia de células falciformes . Lo hizo incubando las células del paciente en un cultivo de tejidos con ADN extraído de un donante con hemoglobina normal . En 1968, los investigadores Theodore Friedmann , Jay Seegmiller y John Subak-Sharpe en los Institutos Nacionales de Salud (NIH), Bethesda, en los Estados Unidos corrigieron con éxito los defectos genéticos asociados con el síndrome de Lesch-Nyhan , una enfermedad neurológica debilitante , al agregar ADN extraño a células cultivadas recolectadas de pacientes que sufrían la enfermedad. [9]

El primer intento, fallido, de terapia genética (así como el primer caso de transferencia médica de genes extraños a humanos sin contar el trasplante de órganos ) fue realizado por el genetista Martin Cline de la Universidad de California en Los Ángeles en California , Estados Unidos el 10 de julio de 1980. [10] [11] Cline afirmó que uno de los genes de sus pacientes estaba activo seis meses después, aunque nunca publicó estos datos ni los hizo verificar. [12]

Después de una extensa investigación en animales durante la década de 1980 y un ensayo de marcado genético bacteriano en humanos en 1989, la primera terapia genética ampliamente aceptada como un éxito se demostró en un ensayo que comenzó el 14 de septiembre de 1990, cuando Ashanthi DeSilva fue tratada por ADA - SCID . [13]

El primer tratamiento somático que produjo un cambio genético permanente se inició en 1993. [14] El objetivo era curar los tumores cerebrales malignos mediante el uso de ADN recombinante para transferir un gen que hiciera que las células tumorales fueran sensibles a un fármaco que, a su vez, causaría la muerte de las células tumorales. [15]

Los polímeros se traducen en proteínas , interfieren con la expresión de genes diana o posiblemente corrigen mutaciones genéticas . La forma más común utiliza ADN que codifica un gen terapéutico funcional para reemplazar un gen mutado . La molécula de polímero se empaqueta dentro de un " vector ", que transporta la molécula dentro de las células. [ cita médica necesaria ]

Los primeros fracasos clínicos llevaron a que se descartara la terapia génica. Los éxitos clínicos desde 2006 recuperaron la atención de los investigadores, aunque a partir de 2014 , todavía era en gran medida una técnica experimental. [16] Estos incluyen el tratamiento de enfermedades de la retina, amaurosis congénita de Leber [17] [18] [19] [20] y coroideremia , [21] SCID ligada al cromosoma X , [22] ADA-SCID, [23] [24] adrenoleucodistrofia , [25] leucemia linfocítica crónica (LLC), [26] leucemia linfocítica aguda (LLA), [27] mieloma múltiple , [28] hemofilia , [24] y enfermedad de Parkinson . [29] Entre 2013 y abril de 2014, las empresas estadounidenses invirtieron más de $600 millones en el campo. [30]

La primera terapia génica comercial, Gendicine , fue aprobada en China en 2003, para el tratamiento de ciertos tipos de cáncer. [31] En 2011, Neovasculgen fue registrado en Rusia como el primer fármaco de terapia génica de su clase para el tratamiento de la enfermedad arterial periférica , incluida la isquemia crítica de las extremidades . [32] En 2012, alipogen tiparvovec , un tratamiento para un trastorno hereditario poco común , la deficiencia de lipoproteína lipasa , se convirtió en el primer tratamiento en ser aprobado para uso clínico en la Unión Europea o los Estados Unidos después de su aprobación por la Comisión Europea . [16] [33]

Tras los primeros avances en ingeniería genética de bacterias, células y pequeños animales, los científicos comenzaron a considerar cómo aplicarla a la medicina. Se consideraron dos enfoques principales: reemplazar o alterar los genes defectuosos. [34] Los científicos se centraron en enfermedades causadas por defectos de un solo gen, como la fibrosis quística , la hemofilia, la distrofia muscular , la talasemia y la anemia de células falciformes . Alipogene tiparvovec trata una de esas enfermedades, causada por un defecto en la lipoproteína lipasa . [33]

El ADN debe administrarse, llegar a las células dañadas, ingresar a la célula y expresar o alterar una proteína. [35] Se han explorado múltiples técnicas de administración. El enfoque inicial incorporaba ADN en un virus diseñado para administrar el ADN en un cromosoma . [36] [37] También se han explorado enfoques de ADN desnudo , especialmente en el contexto del desarrollo de vacunas . [38]

En general, los esfuerzos se centraron en administrar un gen que provoca la expresión de una proteína necesaria. Más recientemente, una mayor comprensión de la función de las nucleasas ha llevado a una edición de ADN más directa, utilizando técnicas como las nucleasas de dedo de zinc y CRISPR . El vector incorpora genes en los cromosomas. Las nucleasas expresadas luego eliminan y reemplazan los genes en el cromosoma. A partir de 2014, estos enfoques implican la extracción de células de los pacientes, la edición de un cromosoma y la devolución de las células transformadas a los pacientes. [39]

La edición genética es un enfoque potencial para alterar el genoma humano con el fin de tratar enfermedades genéticas, [40] enfermedades virales, [41] y cáncer. [42] [43] A partir de 2020, estos enfoques se están estudiando en ensayos clínicos. [44] [45]

Clasificación

Amplitud de la definición

En 1986, una reunión en el Instituto de Medicina definió la terapia génica como la adición o reemplazo de un gen en un tipo de célula objetivo. Ese mismo año, la FDA anunció que tenía jurisdicción para aprobar la "terapia génica" sin definir el término. La FDA agregó una definición muy amplia en 1993 de cualquier tratamiento que "modifique o manipule la expresión de material genético o altere las propiedades biológicas de las células vivas". En 2018, esto se redujo a "productos que median sus efectos mediante la transcripción o traducción de material genético transferido o alterando específicamente las secuencias genéticas del huésped (humano)". [46]

En un artículo publicado en 2018 en el Journal of Law and the Biosciences, Sherkow et al. abogaron por una definición más estricta de terapia génica que la de la FDA a la luz de la nueva tecnología que consistiría en cualquier tratamiento que modifique intencional y permanentemente el genoma de una célula, y la definición de genoma incluiría los episomas fuera del núcleo, pero excluiría los cambios debidos a los episomas que se pierden con el tiempo. Esta definición también excluiría la introducción de células que no derivaran de un paciente en sí, pero incluiría enfoques ex vivo y no dependería del vector utilizado. [46]

Durante la pandemia de COVID-19 , algunos académicos insistieron en que las vacunas de ARNm para COVID no eran terapia genética para prevenir la propagación de información incorrecta de que la vacuna podría alterar el ADN, otros académicos sostuvieron que las vacunas eran una terapia genética porque introducían material genético en una célula. [47] Los verificadores de hechos , como Full Fact , [48] Reuters , [49] PolitiFact , [50] y FactCheck.org [51] dijeron que llamar a las vacunas una terapia genética era incorrecto. El presentador de podcast Joe Rogan fue criticado por llamar a las vacunas de ARNm una terapia genética, al igual que el político británico Andrew Bridgen , y el verificador de hechos Full Fact pidió que se expulsara a Bridgen del partido conservador por esta y otras declaraciones. [52] [53]

Genes presentes o añadidos

La terapia génica encapsula muchas formas de agregar diferentes ácidos nucleicos a una célula. La amplificación génica agrega un nuevo gen codificador de proteínas a una célula. Una forma de amplificación génica es la terapia de reemplazo génico , un tratamiento para trastornos monogénicos recesivos en los que un solo gen no es funcional y se agrega un gen funcional adicional. Para enfermedades causadas por múltiples genes o un gen dominante, los enfoques de silenciamiento génico o edición génica son más apropiados, pero la adición génica , una forma de amplificación génica en la que se agrega un nuevo gen, puede mejorar la función de una célula sin modificar los genes que causan un trastorno. [54] : 117 

Tipos de células

La terapia genética se puede clasificar en dos tipos según el tipo de célula que afecta: terapia génica de células somáticas y terapia génica de línea germinal.

En la terapia génica de células somáticas (SCGT), los genes terapéuticos se transfieren a cualquier célula que no sea un gameto , célula germinal , gametocito o célula madre indiferenciada . Cualquier modificación de este tipo afecta solo al paciente individual y no se hereda a la descendencia . La terapia génica somática representa la investigación básica y clínica convencional, en la que se utiliza ADN terapéutico (ya sea integrado en el genoma o como un episoma externo o plásmido ) para tratar enfermedades. [55] Más de 600 ensayos clínicos que utilizan SCGT están en marcha [ ¿cuándo? ] en los EE. UU. La mayoría se centra en trastornos genéticos graves, incluidas inmunodeficiencias , hemofilia , talasemia y fibrosis quística . Estos trastornos de un solo gen son buenos candidatos para la terapia de células somáticas. La corrección completa de un trastorno genético o el reemplazo de múltiples genes aún no es posible. Solo unos pocos de los ensayos están en etapas avanzadas. [56] [ necesita actualización ]

En la terapia génica de línea germinal (GGT), las células germinales ( espermatozoides u óvulos ) se modifican mediante la introducción de genes funcionales en sus genomas. La modificación de una célula germinal hace que todas las células del organismo contengan el gen modificado. Por lo tanto, el cambio es hereditario y se transmite a las generaciones posteriores. Australia, Canadá, Alemania, Israel, Suiza y los Países Bajos [57] prohíben la GGT para su aplicación en seres humanos, por razones técnicas y éticas, incluido el conocimiento insuficiente sobre los posibles riesgos para las generaciones futuras [57] y los riesgos más altos frente a la SCGT. [58] Estados Unidos no tiene controles federales que aborden específicamente la modificación genética humana (más allá de las regulaciones de la FDA para terapias en general). [57] [59] [60] [61]

Terapias in vivo versus ex vivo

Terapia génica ex vivo

En la terapia génica in vivo , se introduce un vector (normalmente, un virus) en el paciente, que luego logra el efecto biológico deseado al pasar el material genético (por ejemplo, para una proteína faltante) a las células del paciente. En las terapias génicas ex vivo , como las terapias CAR-T , las propias células del paciente (autólogas) o las células sanas de un donante (alogénicas) se modifican fuera del cuerpo (es decir, ex vivo ) utilizando un vector para expresar una proteína particular, como un receptor de antígeno quimérico. [62]

La terapia génica in vivo se considera más sencilla, ya que no requiere la recolección de células mitóticas . Sin embargo, las terapias génicas ex vivo se toleran mejor y están menos asociadas a respuestas inmunitarias graves. [63] La muerte de Jesse Gelsinger en un ensayo de un tratamiento con adenovirus para la deficiencia de ornitina transcarbamilasa debido a una reacción inflamatoria sistémica provocó una suspensión temporal de los ensayos de terapia génica en los Estados Unidos. [64] A partir de 2021 , tanto las terapias in vivo como ex vivo se consideran seguras. [65]

Edición genética

Un dúplex de crRNA y tracrRNA actúa como ARN guía para introducir una modificación genética específicamente ubicada en función del ARN 5' aguas arriba del crRNA. Cas9 se une al tracrRNA y necesita una secuencia de unión al ADN (5'NGG3'), que se denomina motivo adyacente al protoespaciador (PAM). Después de la unión, Cas9 introduce una rotura de doble cadena de ADN, a la que luego le sigue una modificación genética mediante recombinación homóloga (HDR) o unión de extremos no homólogos (NHEJ).

El concepto de la terapia génica consiste en solucionar un problema genético desde su origen. Si, por ejemplo, una mutación en un gen determinado provoca la producción de una proteína disfuncional que da lugar (normalmente de forma recesiva) a una enfermedad hereditaria, se podría utilizar la terapia génica para introducir una copia de ese gen que no contenga la mutación perjudicial y, por tanto, produzca una proteína funcional. Esta estrategia se denomina terapia de sustitución génica y podría emplearse para tratar enfermedades hereditarias de la retina. [17] [66]

Si bien el concepto de terapia de reemplazo genético es adecuado en su mayoría para enfermedades recesivas, se han sugerido nuevas estrategias que también pueden tratar afecciones con un patrón de herencia dominante.

In vivo, los sistemas de edición genética que utilizan CRISPR se han utilizado en estudios con ratones para tratar el cáncer y han resultado eficaces para reducir los tumores. [72] : 18  In vitro, el sistema CRISPR se ha utilizado para tratar tumores cancerosos causados ​​por el VPH. Se han utilizado vectores basados ​​en lentivirus y virus adenoasociados para introducir el genoma en el sistema CRISPR. [72] : 6 

Vectores

La introducción de ADN en las células se puede realizar mediante diversos métodos . Las dos clases principales son los virus recombinantes (a veces llamados nanopartículas biológicas o vectores virales) y el ADN desnudo o los complejos de ADN (métodos no virales). [73]

Virus

Terapia génica con un vector de adenovirus . En algunos casos, el adenovirus insertará el nuevo gen en una célula. Si el tratamiento tiene éxito, el nuevo gen generará una proteína funcional para tratar una enfermedad.

Para replicarse , los virus introducen su material genético en la célula huésped, engañando a la maquinaria celular del huésped para que lo utilice como modelo para las proteínas virales. [54] : 39  Los retrovirus van un paso más allá al tener su material genético copiado en el genoma nuclear de la célula huésped. Los científicos explotan esto sustituyendo parte del material genético de un virus con ADN o ARN terapéutico. [54] : 40  [74] Al igual que el material genético (ADN o ARN) en los virus, el material genético terapéutico puede diseñarse para que simplemente sirva como un modelo temporal que se degrada naturalmente, como en los vectores no integrativos , o para entrar en el núcleo del huésped y convertirse en una parte permanente del ADN nuclear del huésped en las células infectadas. [54] : 50 

Se han utilizado varios virus para la terapia génica humana, incluidos virus como el lentivirus , el adenovirus , el herpes simple , el virus vaccinia y el virus adenoasociado . [5]

Los vectores virales de adenovirus (Ad) modifican temporalmente la expresión genética de una célula con material genético que no está integrado en el ADN de la célula huésped. [75] : 5  A partir de 2017, dichos vectores se utilizaron en el 20% de los ensayos de terapia génica. [74] : 10  Los vectores de adenovirus se utilizan principalmente en tratamientos contra el cáncer y nuevas vacunas genéticas como la vacuna contra el ébola , vacunas utilizadas en ensayos clínicos para el VIH y el SARS-CoV-2 , o vacunas contra el cáncer . [75] : 5 

Los vectores lentivirales basados ​​en lentivirus , un retrovirus , pueden modificar el genoma nuclear de una célula para expresar permanentemente un gen, aunque los vectores pueden modificarse para evitar la integración. [54] : 40,50  Los retrovirus se utilizaron en el 18% de los ensayos antes de 2018. [74] : 10  Libmeldy es un tratamiento con células madre ex vivo para la leucodistrofia metacromática que utiliza un vector lentiviral y fue aprobado por la agencia médica europea en 2020. [76]

El virus adenoasociado (AAV) es un virus que es incapaz de transmitirse entre células a menos que la célula esté infectada por otro virus, un virus auxiliar. El adenovirus y los virus del herpes actúan como virus auxiliares para el AAV. El AAV persiste dentro de la célula fuera del genoma nuclear de la célula durante un período prolongado de tiempo a través de la formación de concatémeros organizados principalmente como episomas . [77] : 4  El material genético de los vectores AAV se integra en el genoma nuclear de la célula huésped a una baja frecuencia y probablemente mediado por las enzimas modificadoras del ADN de la célula huésped. [78] : 2647  Los modelos animales sugieren que la integración del material genético del AAV en el genoma nuclear de la célula huésped puede causar carcinoma hepatocelular , una forma de cáncer de hígado . [78] Se han explorado varios agentes de investigación de AAV en el tratamiento de la degeneración macular húmeda relacionada con la edad mediante enfoques tanto intravítreos como subretinales como una posible aplicación de la terapia génica de AAV para la enfermedad humana. [79] [80]

No viral

Los vectores no virales para terapia génica [81] presentan ciertas ventajas sobre los métodos virales, como la producción a gran escala y la baja inmunogenicidad del huésped . Sin embargo, los métodos no virales inicialmente produjeron niveles más bajos de transfección y expresión génica y, por lo tanto, una menor eficacia terapéutica. Las tecnologías más nuevas ofrecen la promesa de resolver estos problemas, con el advenimiento de una mayor focalización específica de las células y el control del tráfico subcelular.

Los métodos de terapia génica no viral incluyen la inyección de ADN desnudo, la electroporación , la pistola génica , la sonoporación , la magnetofección , el uso de oligonucleótidos , lipoplexos, dendrímeros y nanopartículas inorgánicas. Estas terapias se pueden administrar directamente o mediante enriquecimiento de andamiajes . [82] [83]

Enfoques más recientes, como los realizados por empresas como Ligandal, ofrecen la posibilidad de crear tecnologías de focalización celular específica para una variedad de modalidades de terapia génica, incluyendo ARN, ADN y herramientas de edición genética como CRISPR. Otras empresas, como Arbutus Biopharma y Arcturus Therapeutics , ofrecen enfoques no virales y no dirigidos a células que exhiben principalmente trofismo hepático. En años más recientes, empresas emergentes como Sixfold Bio, GenEdit y Spotlight Therapeutics han comenzado a resolver el problema de la administración de genes no virales. Las técnicas no virales ofrecen la posibilidad de dosificación repetida y una mayor adaptabilidad de las cargas útiles genéticas, que en el futuro tendrán más probabilidades de tomar el control de los sistemas de administración basados ​​en virus.

Empresas como Editas Medicine , Intellia Therapeutics , CRISPR Therapeutics , Casebia, Cellectis , Precision Biosciences , bluebird bio , Excision BioTherapeutics y Sangamo han desarrollado técnicas de edición genética no viral, pero aún utilizan con frecuencia virus para introducir material genético después de la escisión genómica mediante nucleasas guiadas . Estas empresas se centran en la edición genética y aún enfrentan importantes obstáculos para su distribución.

BioNTech , Moderna Therapeutics y CureVac se centran en la administración de cargas útiles de ARNm , que necesariamente presentan problemas de administración no virales.

Alnylam , Dicerna Pharmaceuticals e Ionis Pharmaceuticals se centran en la administración de ARNi (oligonucleótidos antisentido) para la supresión genética, lo que también requiere sistemas de administración no virales.

En contextos académicos, varios laboratorios están trabajando en la administración de partículas pegiladas , que forman coronas de proteínas séricas y exhiben principalmente una captación mediada por el receptor de LDL en células in vivo . [84]

Tratamiento

Cáncer

Terapia génica directa
Gráfica de terapia génica suicida utilizada para tratar el cáncer

Se han realizado intentos de tratar el cáncer mediante terapia génica. En 2017, el 65 % de los ensayos de terapia génica se realizaron para el tratamiento del cáncer. [74] : 7 

Los vectores de adenovirus son útiles para algunas terapias génicas contra el cáncer porque el adenovirus puede insertar material genético transitoriamente en una célula sin alterar permanentemente el genoma nuclear de la célula. Estos vectores se pueden utilizar para hacer que se añadan antígenos a los cánceres provocando una respuesta inmunitaria o para obstaculizar la angiogénesis mediante la expresión de determinadas proteínas. [85] : 5  Un vector de adenovirus se utiliza en los productos comerciales Gendicine y Oncorine . [85] : 10  Otro producto comercial, Rexin G , utiliza un vector basado en retrovirus y se une selectivamente a los receptores que se expresan más en los tumores. [85] : 10 

Un enfoque, la terapia génica suicida , funciona introduciendo genes que codifican enzimas que harán que una célula cancerosa muera. Otro enfoque es el uso de virus oncolíticos , como Oncorine, [86] : 165  que son virus que se reproducen selectivamente en células cancerosas sin afectar a otras células. [87] : 6  [88] : 280 

Se ha sugerido el ARNm como un vector no viral para la terapia génica del cáncer que cambiaría temporalmente la función de una célula cancerosa para crear antígenos o matar las células cancerosas y se han realizado varios ensayos. [89]

Afamitresgene autoleucel , comercializado bajo la marca Tecelra, es una inmunoterapia autóloga de células T que se utiliza para el tratamiento del sarcoma sinovial . Es una terapia génica del receptor de células T (TCR). [90] Es la primera terapia celular diseñada aprobada por la FDA para un tumor sólido. [91] Utiliza un vector lentiviral autoinactivante para expresar un receptor de células T específico para MAGE-A4, un antígeno asociado al melanoma. [ cita médica requerida ]

Enfermedades genéticas

Se han propuesto enfoques de terapia génica para reemplazar un gen defectuoso por un gen sano y se están estudiando para tratar algunas enfermedades genéticas. En 2017, el 11,1 % de los ensayos clínicos de terapia génica se dirigieron a enfermedades monogénicas. [74] : 9 

Las enfermedades como la anemia de células falciformes , que son causadas por trastornos autosómicos recesivos en los que el fenotipo o la función celular normal de una persona se pueden restaurar en las células que tienen la enfermedad mediante una copia normal del gen que está mutado, pueden ser un buen candidato para el tratamiento de terapia génica. [92] [93] No se conocen los riesgos y beneficios relacionados con la terapia génica para la anemia de células falciformes. [93]

La terapia génica se ha utilizado en el ojo . El ojo es especialmente adecuado para los vectores virales adenoasociados . Voretigene neparvovec es una terapia génica aprobada para tratar la neuropatía óptica hereditaria de Leber . [94] : 1354  alipogene tiparvovec , un tratamiento para la pancreatitis causada por una afección genética, y Zolgensma para el tratamiento de la atrofia muscular espinal , ambos utilizan un vector viral adenoasociado. [78] : 2647 

Enfermedades infecciosas

En 2017, el 7% de los ensayos de terapia genética se centraron en enfermedades infecciosas. El 69,2% de los ensayos se centraron en el VIH , el 11% en la hepatitis B o C y el 7,1% en la malaria . [74]

Lista de terapias genéticas para el tratamiento de enfermedades

Algunas terapias genéticas han sido aprobadas por la Administración de Alimentos y Medicamentos de Estados Unidos (FDA), la Agencia Europea de Medicamentos (EMA) y para su uso en Rusia y China.

Efectos adversos, contraindicaciones y obstáculos para su uso

Algunos de los problemas sin resolver incluyen:

Fallecidos

Se han notificado tres muertes de pacientes en ensayos de terapia génica, lo que ha puesto este campo bajo un escrutinio minucioso. El primero fue el de Jesse Gelsinger , que murió en 1999, debido a una respuesta de rechazo inmunológico. [126] [127] Un paciente con X-SCID murió de leucemia en 2003. [13] En 2007, un paciente con artritis reumatoide murió a causa de una infección; la investigación posterior concluyó que la muerte no estaba relacionada con la terapia génica. [128]

Reglamento

Las normas que regulan la modificación genética forman parte de las directrices generales sobre la investigación biomédica en la que participan seres humanos. [ cita requerida ] No existen tratados internacionales que sean jurídicamente vinculantes en esta área, pero sí hay recomendaciones de leyes nacionales de varios organismos. [ cita requerida ]

La Declaración de Helsinki (Principios éticos para la investigación médica en seres humanos) fue enmendada por la Asamblea General de la Asociación Médica Mundial en 2008. Este documento proporciona principios que los médicos e investigadores deben considerar cuando se involucran seres humanos como sujetos de investigación. La Declaración sobre la investigación en terapia génica iniciada por la Organización del Genoma Humano (HUGO) en 2001, proporciona una base legal para todos los países. El documento de HUGO enfatiza la libertad humana y la adhesión a los derechos humanos, y ofrece recomendaciones para la terapia génica somática, incluida la importancia de reconocer las preocupaciones públicas sobre este tipo de investigación. [129]

Estados Unidos

Ninguna legislación federal establece protocolos o restricciones sobre la ingeniería genética humana. Este tema está regido por regulaciones superpuestas de agencias locales y federales, incluyendo el Departamento de Salud y Servicios Humanos , la FDA y el Comité Asesor de ADN Recombinante del NIH. Los investigadores que buscan fondos federales para una solicitud de investigación de un nuevo fármaco (que es común en el caso de la ingeniería genética humana somática) deben obedecer las pautas internacionales y federales para la protección de los sujetos humanos. [130]

El NIH es el principal regulador de la terapia génica para la investigación financiada por el gobierno federal. Se recomienda que la investigación financiada con fondos privados cumpla con estas normas. El NIH proporciona financiación para la investigación que desarrolla o mejora las técnicas de ingeniería genética y para evaluar la ética y la calidad de la investigación actual. El NIH mantiene un registro obligatorio de protocolos de investigación de ingeniería genética humana que incluye todos los proyectos financiados por el gobierno federal. [131]

Un comité asesor del NIH publicó un conjunto de directrices sobre manipulación genética. [132] Las directrices tratan de la seguridad en el laboratorio, así como de los sujetos de prueba humanos y de varios tipos de experimentos que implican cambios genéticos. Varias secciones se refieren específicamente a la ingeniería genética humana, incluida la Sección III-C-1. Esta sección describe los procesos de revisión necesarios y otros aspectos a la hora de solicitar la aprobación para iniciar una investigación clínica que implique la transferencia genética a un paciente humano. [133] El protocolo para un ensayo clínico de terapia genética debe ser aprobado por el Comité Asesor de ADN Recombinante del NIH antes de que comience cualquier ensayo clínico; esto es diferente de cualquier otro tipo de ensayo clínico. [132]

As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[134][135]

Gene doping

Athletes may adopt gene therapy technologies to improve their performance.[136] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[137]

Genetic enhancement

Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[138][139][140] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[141][142] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[143]

A 2020 issue of the journal Bioethics was devoted to moral issues surrounding germline genetic engineering in people.[144]

Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Association's Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."[145]

As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[146] and such concerns have continued as technology progressed.[147][148] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[149][150][151][152] In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[153][154] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[155][156] once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."[157]

History

1970s and earlier

In 1972, Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?".[158] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those with genetic defects.[159]

1980s

In 1984, a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[160]

1990s

The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[161] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with adenosine deaminase deficiency (ADA-SCID), a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti's immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[162]

Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[163] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocol no.1602 24 November 1993,[164] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

In 1992, Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[165] In 2002, this work led to the publication of the first successful gene therapy treatment for ADA-SCID. The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[166]

In 1993, Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[167]

In 1996, Luigi Naldini and Didier Trono developed a new class of gene therapy vectors based on HIV capable of infecting non-dividing cells that have since then been widely used in clinical and research settings, pioneering lentivirals vector in gene therapy.[168]

Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[169][170] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[171]

2000s

The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602)[164] using antisense / triple helix anti-IGF-I approach was registered in 2002, by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

2002

Sickle cell disease can be treated in mice.[172] The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[173]

A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[174]

Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[175]

2003

In 2003, a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the blood–brain barrier.[176]

Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[177]

Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[31]

2006

In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[178]

In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene.[179] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

In August, scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[180]

In November, researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[181][182]

2007

In May 2007, researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[183]

2008

Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[17] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May, two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[17][18][19][20]

2009

In September researchers were able to give trichromatic vision to squirrel monkeys.[184] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[185]

2010s

2010

An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[186]

In September it was announced that an 18-year-old male patient in France with beta thalassemia major had been successfully treated.[187] Beta thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[188] The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and marrow cells obtained from the patient in June 2007.[189] The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[189][190] Further clinical trials were planned.[191] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[190]

Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[192][193]

2011

In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[194] It required complete ablation of existing bone marrow, which is very debilitating.[195]

In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[26] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[196]

Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[197][198]

In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[32] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[199][200]

2012

The FDA approved Phase I clinical trials on thalassemia major patients in the US for 10 participants in July.[201] The study was expected to continue until 2015.[191]

In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[202] The recommendation was endorsed by the European Commission in November 2012,[16][33][203][204] and commercial rollout began in late 2014.[205] Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[206] revised to $1 million in 2015,[207] making it the most expensive medicine in the world at the time.[208] As of 2016, only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug.[209]

In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[28]

2013

In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T cells and B cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[27]

Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[210] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[211] The U.S. Food and Drug Administration (FDA) granted this a breakthrough therapy designation to accelerate the trial and approval process.[212] In 2016, it was reported that no improvement was found from the CUPID 2 trial.[213]

In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[214] The other children had Wiskott–Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[215] Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.[216][217]

In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[24] In 2014, a further 18 children with ADA-SCID were cured by gene therapy.[218] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children".[24]

Also in October researchers reported that they had treated six people with haemophilia in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.[24][219]

2014

In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight.[66][220] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[21] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[221][222]

Clinical trials of gene therapy for sickle cell disease were started in 2014.[223][224]

In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[225]

In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[226][227]

In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".[149][150][151][152]

In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[228] but that basic research including embryo gene editing should continue.[229]

2015

Researchers successfully treated a boy with epidermolysis bullosa using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease.[230]

In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[231] Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.[232][233]

2016

In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[234][235] and the European Commission approved it in June.[236] This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.[237]

In October, Chinese scientists reported they had started a trial to genetically modify T cells from 10 adult patients with lung cancer and reinject the modified T cells back into their bodies to attack the cancer cells. The T cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[238][239]

A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[240]

2017

In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced non-Hodgkin lymphoma.[241]

In March, French scientists reported on clinical research of gene therapy to treat sickle cell disease.[242]

In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[243] Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[244]

In October, biophysicist and biohacker Josiah Zayner claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy.[245][246]

On 13 November, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever in-body human gene editing therapy.[247][248] The treatment, designed to permanently insert a healthy version of the flawed gene that causes Hunter syndrome, was given to 44-year-old Brian Madeux and is part of the world's first study to permanently edit DNA inside the human body.[249] The success of the gene insertion was later confirmed.[250][251] Clinical trials by Sangamo involving gene editing using zinc finger nuclease (ZFN) are ongoing.[252]

In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.[253][254]

In December, the FDA approved voretigene neparvovec, the first in vivo gene therapy, for the treatment of blindness due to Leber's congenital amaurosis.[255] The price of this treatment is US$850,000 for both eyes.[256][257]

2019

In May, the FDA approved onasemnogene abeparvovec (Zolgensma) for treating spinal muscular atrophy in children under two years of age. The list price of Zolgensma was set at US$2.125 million per dose, making it the most expensive drug ever.[258]

In May, the EMA approved betibeglogene autotemcel (Zynteglo) for treating beta thalassemia for people twelve years of age and older.[259][260]

In July, Allergan and Editas Medicine announced phase I/II clinical trial of AGN-151587 for the treatment of Leber congenital amaurosis 10.[261] This is one of the first studies of a CRISPR-based in vivo human gene editing therapy, where the editing takes place inside the human body.[262] The first injection of the CRISPR-Cas System was confirmed in March 2020.[263]

Exagamglogene autotemcel, a CRISPR-based human gene editing therapy, was used for sickle cell and thalassemia in clinical trials.[264]

2020s

2020

In May, onasemnogene abeparvovec (Zolgensma) was approved by the European Union for the treatment of spinal muscular atrophy in people who either have clinical symptoms of SMA type 1 or who have no more than three copies of the SMN2 gene, irrespective of body weight or age.[265]

In August, Audentes Therapeutics reported that three out of 17 children with X-linked myotubular myopathy participating the clinical trial of a AAV8-based gene therapy treatment AT132 have died. It was suggested that the treatment, whose dosage is based on body weight, exerts a disproportionately toxic effect on heavier patients, since the three patients who died were heavier than the others.[266][267] The trial has been put on clinical hold.[268]

On 15 October, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the "late infantile" (LI) or "early juvenile" (EJ) forms of metachromatic leukodystrophy (MLD).[269] The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene.[269] When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body.[270] Libmeldy was approved for medical use in the EU in December 2020.[271]

On 15 October, Lysogene, a French biotechnological company, reported the death of a patient in who has received LYS-SAF302, an experimental gene therapy treatment for mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A).[272]

2021

In May, a new method using an altered version of HIV as a lentivirus vector was reported in the treatment of 50 children with ADA-SCID obtaining positive results in 48 of them,[273][274][275] this method is expected to be safer than retroviruses vectors commonly used in previous studies of SCID where the development of leukemia was usually observed[276] and had already been used in 2019, but in a smaller group with X-SCID.[277][278][279][280]

In June a clinical trial on six patients affected with transthyretin amyloidosis reported a reduction the concentration of missfolded transthretin (TTR) protein in serum through CRISPR-based inactivation of the TTR gene in liver cells observing mean reductions of 52% and 87% among the lower and higher dose groups.This was done in vivo without taking cells out of the patient to edit them and reinfuse them later.[281][282][283]

In July results of a small gene therapy phase I study was published reporting observation of dopamine restoration on seven patients between 4 and 9 years old affected by aromatic L-amino acid decarboxylase deficiency (AADC deficiency).[284][285][286]

2022

In February, the first ever gene therapy for Tay–Sachs disease was announced, it uses an adeno-associated virus to deliver the correct instruction for the HEXA gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.[287][288][289]

In May, eladocagene exuparvovec is recommended for approval by the European Commission.[290][291]

In July results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.[292][293][294]

In December, a 13-year girl that had been diagnosed with T-cell acute lymphoblastic leukaemia was successfully treated at Great Ormond Street Hospital (GOSH) in the first documented use of therapeutic gene editing for this purpose, after undergoing six months of an experimental treatment, where all attempts of other treatments failed. The procedure included reprogramming a healthy T-cell to destroy the cancerous T-cells to first rid her of leukaemia, and then rebuilding her immune system using healthy immune cells.[295] The GOSH team used BASE editing and had previously treated a case of acute lymphoblastic leukaemia in 2015 using TALENs.[233]

2023

In May 2023, the FDA approved beremagene geperpavec for the treatment of wounds in people with dystrophic epidermolysis bullosa (DEB) which is applied as a topical gel that delivers a herpes-simplex virus type 1 (HSV-1) vector encoding the collagen type VII alpha 1 chain (COL7A1) gene that is dysfunctional on those affected by DEB . One trial found 65% of the Vyjuvek-treated wounds completely closed while only 26% of the placebo-treated at 24 weeks.[97] It has been also reported its use as a eyedrops for a patient with DEB that had vision loss due to the widespread blistering with good results.[296]

In June 2023, the FDA gave an accelerated approval to Elevidys for Duchenne muscular dystrophy (DMD) only for boys 4 to 5 years old as they are more likely to benefit from the therapy which consists of one-time intravenous infusion of a virus (AAV rh74 vector) that delivers a functioning "microdystrophin" gene (138 kDa) into the muscle cells to act in place of the normal dystrophin (427 kDa) that is found mutated in this disease.[102]

In July 2023, it was reported that it had been developed a new method to affect genetic expressions through direct current.[297]

List of gene therapies

References

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Further reading

External links

Wikibooks has a book on the topic of: Genes, Technology and Policy
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