ES2572830T3 - Métodos para seleccionar ovocitos y embriones competentes con elevado potencial de resultado de embarazo - Google Patents
Métodos para seleccionar ovocitos y embriones competentes con elevado potencial de resultado de embarazo Download PDFInfo
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Abstract
Un método para seleccionar un ovocito que, una vez fecundado, produce un embrión viable con una elevada tasa de implantación que produce embarazo: que comprende una etapa de medición, en una célula del cumulus que rodea dicho ovocito, del nivel de expresión de los genes de los grupos A, B y C, en los que: - el grupo A consiste en fosfoenolpiruvato carboxiquinasa 1 (PCK1), ADP-ribosilarginina hidrolasa (ADPRH), proteína de unión a calcio 4 (CABP4), miembro 6 de la familia SLAM (SLAMF6), activador de transcripción 1 de unión a calmodulina (CAMTA1), proteoglicano condroitín sulfato 2 (CSPG2), y perforina 1 (PRF1), - el grupo B consiste en el homólogo B del oncogén viral de osteosarcoma murino FBJ (FOSB), neuroligina 2 (NLGN2), fosfodiesterasa 5A específica para GMPc (PDE5A), fosfolipasa A2 del grupo V (PLA2G5), glipicano 6 (GPC6), y gen de respuesta al crecimiento rápido 3 (EGR 3), y - el grupo C consiste en el factor nuclear I/B (NFIB), factor nuclear I/C (NFIC), receptor 1 del factor de crecimiento semejante a la insulina (IGF1R), conmutador G0/G1 2 (G0S2), receptor ionotrópico de glutamato tipo kainato 5 (GRIK5) y proteína 1 de interacción monocatenaria con motivo de unión a ARN, (RBMS1), - que comprende además una etapa que consiste en comparar el nivel de expresión de los genes en la muestra con un control, en el que: - la sobreexpresión de uno o más genes seleccionados entre el grupo A permite predecir que un ovocito, una vez fecundado, produce un embrión viable con una elevada tasa de implantación que produce embarazo, - la sobreexpresión de uno o más genes seleccionados entre el grupo B permite predecir que un ovocito, una vez fecundado, no produce un embrión viable con una elevada tasa de implantación que produce embarazo, siendo el embrión incapaz de implantarse, - la sobreexpresión de uno o más genes seleccionados entre el grupo C permite predecir que un ovocito, una vez fecundado, no produce un embrión viable con una elevada tasa de implantación que produce embarazo debido a la detención prematura del embrión.
Description
La presente divulgación también se refiere a un método para seleccionar un embrión con una elevada tasa de implantación que produce embarazo, comprende una etapa de medición del nivel de expresión de 45 genes en una célula del cumulus que rodea el embrión, en la que dichos genes son WNT6, LRCH4, PAX8, CABP4, PDE5A, BCL2L11, PCK1, TCF20, SLAMF6, EPOR, CACNG6, NLRP1, PECAM1, NOS1, ATF3, KRTAP8, GRIK5, SLC24A3,
5 SLC5A12, SLCA10A2, SLCO1A2, SLC25A5, MG29, NLGN2, PRKACA, FOSB, SIAT6, LOXL2, PRF1, ADPRH, APBB3, EGR3, CNR2, IFITM1, PLA2G5, CAMTA1, SOX4, NFIB, NFIC, RBMS1, G0S2, FAT3, SLC40A1, GPC6 e IGF1R,
-que comprende además una etapa que consiste en comparar el nivel de expresión de los genes en la
10 muestra con un control, en el que la detección diferencial en el nivel de expresión de los genes entre la muestra y el control refleja si el embrión es competente.
La presente invención se refiere a un método para seleccionar un ovocito que, una vez fecundado, produce un embrión viable con una elevada tasa de implantación que produce embarazo o para seleccionar un embrión con una
15 elevada tasa de implantación que produce embarazo, comprende una etapa de medición, en una célula del cumulus que rodea dicho ovocito o dicho embrión, del nivel de expresión de uno o más genes seleccionados entre los grupos A, B o C, en los que el grupo A consiste en PCK1, ADPRH, CABP4, SLAMF6, CAMTA1, CSPG2, y PRF1; el grupo B consiste en FOSB, NLGN2, PDE5A, PLA2G5, GPC6, y EGR3; y el grupo C consiste en NFIB, NFIC, IGF1R, G0S2, GRIK5 y RBMS1.
20 La sobreexpresión de uno o más genes seleccionados entre el grupo A permite predecir que un ovocito o embrión competente produce embarazo. La sobreexpresión de uno o más genes seleccionados entre el grupo B permite predecir un ovocito o embrión no competente, siendo el embrión incapaz de implantarse. La sobreexpresión de uno
o más genes seleccionados entre el grupo C permite predecir un ovocito o embrión no competente debido a la 25 detención prematura del embrión.
Los inventores han determinado que un conjunto de genes expresados en células del cumulus son biomarcadores
30 para el potencial del embrión y el resultado de embarazo. Se demostró que el perfil de expresión génica de las células del cumulus que rodean los ovocitos se relacionaba con diferentes resultados de embarazo, permitiendo la identificación de una firma de expresión específica de embriones que se desarrollan con respecto al embarazo. Sus resultados indican que el análisis de las células del cumulus que rodean el ovocito es un enfoque no invasivo para la selección de embriones.
35
Todos los genes pertenecientes a la invención se conocen per se, y se enumeran en las siguientes Tablas A y B. Las Tablas A y B presentan el conjunto de genes cuyo perfil de expresión combinado ha demostrado ser de carácter 40 informativo para seleccionar un ovocito competente o para seleccionar un embrión competente con un elevado potencial de implantación que produce embarazo.
Tabla A: conjunto de genes predictivos.
- Símbolo del gen
- Nombre del gen n.º de identificación del gen
- WNT6
- miembro 6 de la familia tipo wingless con un sitio de integración para el virus MMTV 7475
- LRCH4
- dominio que contiene repeticiones ricas en leucina y homología calponina (HC) 4034
- PAX8
- caja pareada 8 7849
- CABP4
- proteína de unión a calcio 4 57010
- PDE5A
- fosfodiesterasa 5A específica para GMPc 8654
- BCL2L11
- BCL2 tipo 11 (facilitador de apoptosis) 10018
- PCK1
- fosfoenolpiruvato carboxiquinasa 1 (soluble) 5105
- TCF20
- factor de transcripción 20 (AR1) 6942
- SLAMF6
- miembro 6 de la familia SLAM 114836
- EPOR
- receptor de la eritropoyetina 2057
- CACNG6
- subunidad gamma 6 del canal de calcio dependiente de voltaje 59285
- NLRP1
- familia NLR que contiene el dominio pirina 1 22861
3
- Símbolo del gen
- Nombre del gen n.º de identificación del gen
- PECAM1
- molécula de adhesión de plaquetas/células endoteliales 5175
- NOS1
- óxido nítrico sintasa 1 (neuronal) 4842
- ATF3
- factor de transcripción activador 3 467
- KRTAP8
- proteína 8-1 asociada con queratina 337879
- GRIK5
- receptor ionotrópico de glutamato tipo kainato 5 2901
- SLC24A3
- miembro 3 de la familia de transportadores de solutos 24 (intercambiador de sodio/potasio/calcio) 57419
- SLC5A12
- miembro 12 de la familia de transportadores de solutos 5 (cotransportador de sodio/glucosa) 159963
- SLCA10A2
- miembro 2 de la familia de transportadores de solutos 10 (familia del cotransportador de sodio/ácido biliar) 6555
- SLCO1A2
- miembro 1A2 de la familia de transportadores de solutos para transportador de aniones orgánicos 6579
- SLC25A5
- miembro 5 de la familia de transportadores de solutos 25 (transportador mitocondrial; translocador de nucleótidos de adenina) 292
- MG29 o SYPL2
- sinaptofisina tipo 2 284612
- NLGN2
- neuroligina 2 57555
- PRKACA
- proteína quinasa dependiente de AMPc catalítica alfa 5566
- FOSB
- homólogo B del oncogén viral de osteosarcoma murino FBJ 2354
- SIAT6
- ST3 beta-galactósido alfa-2,3-sialiltransferasa 3 6487
- LOXL2
- lisil oxidasa tipo 2 4017
- PRF1
- perforina 1 (proteína de formación de poros) 5551
- ADPRH
- ADP-ribosilarginina hidrolasa 141
- APBB3
- miembro 3 de la familia B de unión a proteína precursora beta amiloide (A4) 10307
- EGR3
- gen de respuesta al crecimiento rápido 3 1960
- CNR2
- receptor cannabinoide 2 (macrófagos) 1269
- IFITM1
- proteína transmembrana 1 inducida por interferón (9-27) 8519
- PLA2G5
- fosfolipasa A2 del grupo V 5322
- CAMTA1
- activador de transcripción 1 de unión a calmodulina 23261
- SOX4
- SRY (región Y determinante del sexo) caja 4 6659
- NFIB
- factor nuclear I/B 4781
- NFIC
- factor nuclear I/C (factor de transcripción de unión a CCAAT) 4782
- RBMS1
- proteína 1 de interacción monocatenaria con motivo de unión a ARN 5937
- G0S2
- conmutador G0/G1 2 50486
- FAT3
- homólogo 3 del supresor tumoral FAT (Drosophila) 120114
- SLC40A1
- miembro 1 de la familia de transportadores de solutos 40 (transportador regulado por hierro) 30061
- GPC6
- glipicano 6 10082
- IGF1R
- receptor 1 del factor de crecimiento semejante a la insulina 3480
Un objetivo de la divulgación se refiere a un método para seleccionar un ovocito competente, que comprende una etapa de medición del nivel de expresión de 45 genes en una célula del cumulus que rodea dicho ovocito, en la que
4
- Símbolo del gen
- Nombre del gen n.º de identificación del gen
- B: genes cuyas sobreexpresiones permiten predecir embriones incapaces de implantarse
- FOSB
- homólogo B del oncogén viral de osteosarcoma murino FBJ 2354
- NLGN2
- neuroligina 2 57555
- PDE5A
- fosfodiesterasa 5A específica para GMPc 8654
- PLA2G5
- fosfolipasa A2 del grupo V 5322
- GPC6
- glipicano 6 10082
- EGR3
- gen de respuesta al crecimiento rápido 3 1960
- C: genes cuyas sobreexpresiones permiten predecir una detención prematura del embrión
- NFIB
- factor nuclear I/B 4781
- NFIC
- factor nuclear I/C (factor de transcripción de unión a CCAAT) 4782
- IGF1R
- receptor 1 del factor de crecimiento semejante a la insulina 3480
- G0S2
- conmutador G0/G1 2 50486
- GRIK5
- receptor ionotrópico de glutamato tipo kainato 5 2901
- RBMS1
- proteína 1 de interacción monocatenaria con motivo de unión a ARN 5937
5 A lo largo de la presente solicitud, diversas referencias describen el estado de la técnica a la que pertenece la presente invención. Assou, S., Anahory, T., Pantesco, V., Le Carrour, T., Pellestor, F., Klein, B., Reyftmann, L., Dechaud, H., De Vos, J., Hamamah, S. (2006) The human cumulus--oocyte complex gene-expression profile. Hum Reprod, 21, 1705
19.
10 Balaban, B., Urman, B. (2006) Effect of oocyte morphology on embryo development and implantation. Reprod Biomed Online, 12, 608-15. Brison, D.R., Houghton, F.D., Falconer, D., Roberts, S.A., Hawkhead, J., Humpherson, P.G., Lieberman, B.A., Leese, H.J. (2004) Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover. Hum Reprod, 19, 2319-24.
15 Bromer, J.G., Seli, E. (2008) Assessment of embryo viability in assisted reproductive technology: shortcomings of current approaches and the emerging role of metabolomics. Curr Opin Obstet Gynecol, 20, 234-41. Courtois, G., Smahi, A. (2006) NF-kappaB-related genetic diseases. Cell Death Differ, 13, 843-51. de Hoon, M.J., Imoto, S., Nolan, J., Miyano, S. (2004) Open source clustering software. Bioinformatics, 20, 1453
4.
20 Eisen, M.B., Spellman, P.T., Brown, P.O., Botstein, D. (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A, 95, 14863-8. Fenwick, J., Platteau, P., Murdoch, A.P., Herbert, M. (2002) Time from insemination to first cleavage predicts developmental competence of human preimplantation embryos in vitro. Hum Reprod, 17, 407-12. Feuerstein, P., Cadoret, V., Dalbies-Tran, R., Guerif, F., Bidault, R., Royere, D. (2007) Gene expression in human
25 cumulus cells: one approach to oocyte competence. Hum Reprod, 22, 3069-77. Gardner, D.K., Lane, M., Stevens, J., Schoolcraft, W.B. (2001) Noninvasive assessment of human embryo nutrientA consumption as a measure of developmental potential. Fertil Steril, 76, 1175-80. Gasca, S., Pellestor, F., Assou, S., Loup, V., Anahory, T., Dechaud, H., De Vos, J., Hamamah, S. (2007) Identifying new human oocyte marker genes: a microarray approach. Reprod Biomed Online, 14, 175-83.
30 Hamel, M., Dufort, I., Robert, C., Gravel, C., Leveille, M.C., Leader, A., Sirard, M.A. (2008) Identification of differentially expressed markers in human follicular cells associated with competent oocytes. Hum Reprod, 23, 1118-27. Haouzi, D., De Vos, J., Loup, V., Assou, S., Gasca, S., Reyftmann, L., Klein, B., Hamamah, S. (2008) [Oocyte and embryo quality: Do the apoptotic markers have a place in the preimplantation genetic diagnostic?]. Gynecol
35 Obstet Fertil, 36, 730-742. He, B., Chadburn, A., Jou, E., Schattner, E.J., Knowles, D.M., Cerutti, A. (2004) Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL. J Immunol, 172, 3268-79. Kolena, J., Kiss, A., Channing, C.P. (1983) Purification of porcine granulosa cells by continuous Percoll gradient. Experientia, 39, 908-9.
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| EP2643478B1 (en) | 2010-11-24 | 2018-01-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for selecting competent oocytes and competent embryos with high potential for pregnancy outcome |
| WO2012109326A2 (en) * | 2011-02-09 | 2012-08-16 | Temple University-Of The Commonwealth System Of Higher Education | Determination of oocyte quality |
| JP6186353B2 (ja) | 2011-07-01 | 2017-08-23 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | ヒト卵丘細胞の発生ステージを決定するための方法 |
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| WO2013056258A1 (en) * | 2011-10-14 | 2013-04-18 | Gema Diagnostics, Inc. | Genes differentially expressed by cumulus cells and assays using same to identify pregnancy competent oocytes |
| US20140206930A1 (en) * | 2013-01-18 | 2014-07-24 | Inguran, Llc | Twinning with sex sorted sperm |
| CN104450904A (zh) * | 2014-12-02 | 2015-03-25 | 柳州市妇幼保健院 | 利用颗粒细胞端粒长度来判断胚胎发育潜能的方法 |
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