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Results from the first clinical pilot study using maternal spindle transfer indicate that the technique may have value as a treatment for challenging types of infertility and reveal potential limitations when the method is used for avoidance of mitochondrial disorders

The results from the first clinical pilot study of maternal spindle transfer (MST) were published online in the journal, Fertility and Sterility, as an ahead of print version of the article. The project was carried out in Greece, at the Institute of Life-IASO IVF Center, and involved a multidisciplinary team of scientists from internationally renowned institutions: Embryotools (Science Park, Barcelona, Spain); Juno Genetics (UK); the University of Oxford (UK); Oregon Health & Science University (US). The exploratory study provides the first insights into safety and efficacy of maternal spindle transfer in humans, when applied in a context of infertility treatment. The study resulted in the birth of six children to patients with a long history of previous failed in vitro fertilization attempts. The article additionally reveals important information concerning the potential use of MST to reduce the risk of disease transmission in patients carrying pathogenic mitochondrial DNA (mtDNA) mutations.


The egg is the most important element during the first few days of life. Not only does it carry the genetic contribution (DNA) from the mother, but it also contains stores of materials (e.g., RNA, protein, energy supplies and organelles) in its cytoplasm vital for the developing embryo. Poor egg quality is a significant factor contributing to female infertility, for which no effective treatments have been developed. The problem is characterized by repeated failure of eggs to fertilize and/or impaired embryo development. Currently, the only strategy available for patients that produce poor quality eggs is to undergo in vitro fertilization (IVF) treatments using donated eggs or embryos. This approach can help patients achieve a pregnancy, but excludes them from a genetic contribution to their child.

Maternal spindle transfer is an advanced laboratory technique that belongs to the family of methods known collectively as mitochondrial replacement therapies (MRTs). These techniques were originally proposed to avoid the transmission of mitochondrial diseases and their application for this clinical purpose is already permitted in some countries, such as the UK and Australia. The method involves the replacement of the patient’s egg cytoplasm with cytoplasm taken from young donated egg, while retaining the patient’s nuclear genetic material. Accumulating evidence suggests that this process can overcome some problems related to a failure of an egg to support fertilization and embryonic development, while also allowing patients to produce genetically related offspring.

This exploratory pilot study was conducted in Greece after receiving approval from the National Authority of Assisted Reproduction. The research team aimed to explore, for the first time, the clinical feasibility of the maternal spindle transfer technique in a context of infertility treatment. The pilot study started in 2018 and was limited to a cohort of 25 infertile couples that were carefully selected based on their long history of unsuccessful IVF treatments, associated with poor egg quality. The patients had undergone between 3 and 11 previous IVF attempts (average 6.4 per patient) without success. The outcomes monitored in the study included the usual measures of IVF success, as well as other parameters specifically related to the technique, and pediatric follow-up to evaluate the general health of children born following the procedure.

The data obtained during the study is unique, suggesting that the maternal spindle transfer technique might have the potential to help a class of infertile patients that has been extremely difficult to treat with conventional methods. Together, the patients included in the study had undergone a total of 159 previous IVF treatments, in which 423 mature eggs had been collected, but no pregnancies had ever been achieved. A total of 28 maternal spindle transfer attempts were carried out, resulting in the birth of six babies. The health and developmental status of the children (some now close to 4 years old) is unremarkable, providing some reassurance about the safety of the method.

The scientific team monitored the amount of DNA from mitochondria (mtDNA) transferred into the donor egg along with the patient’s spindle and showed that more than 99% of the mtDNA in the embryos produced was from the egg donor. However, in one child born following the procedure the mitochondria from the patient expanded dramatically during development, and by the time of birth had come to represent about 50% of the total in the cells of the child. This is the first time this phenomenon, known as ‘reversal’ has been reported in human embryos. While none of the patients in the study were carriers of mitochondrial disease, the possibility that the small number of mitochondria, unavoidably transferred to the donor oocyte along with the patient’s DNA, could proliferate disproportionately has implications for the use of MRTs to prevent the transmission such disorders. The severity of mtDNA disorders is linked to the proportion of mitochondria derived from the affected patient. The resurgence of a patient’s mitochondria, after they were initially reduced to a tiny population, suggests that some of these treatments might be less than 100% effective.

While the data obtained is encouraging, potentially creating a new therapy for types of infertility that were previously untreatable, the researchers are keen to stress that this was a pilot study, and as such was limited in size and scope. A definitive assessment of the clinical value of the technique must await future larger, controlled and randomized trials.

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Article identification: DOI: https://doi.org/10.1016/j.fertnstert.2023.02.008.

Authors: Nuno Costa-Borges, PhD; Eros Nikitos, MSc; Katharina Späth, PhD; Irene Miguel-Escalada, PhD; Hong Ma, PhD; Klaus Rink, PhD; Clement Coudereau, PhD; Hayley Darby; Amy Koski, MSc; Crystal Van Dyken, PhD; Enric Mestres, PhD; Evmorfia Papakyriakou, MSc; Dominique De Ziegler, MD; George Kontopoulos, MD; Themistoklis Mantzavinos, MD; Ioannis Vasilopoulos, MD; Stylianos Grigorakis, MD; Thomas Prokopakis, MD; Konstantinos Dimitropoulos, MD; Panagiotis Polyzos, MD; Nikolaοs Vlachos, MD; Konstantinos Kostaras, MD; Shoukhrat Mitalipov, PhD; Gloria Calderón, PhD; Panagiotis Psathas, MD; Dagan Wells*, PhD.

Contacts:
Dr. Nuno Costa-Borges
Embryotools, Barcelona, Spain
nuno.borges@embryotools.com

Prof. Dagan Wells
Juno Genetics / University of Oxford
dagan.wells@junogenetics.com

Dr. Shoukhart Mitalipov
Oregon Health & Science University
mitalipo@ohsu.edu

Dr. Panagiotis Psathas
Institute of Life-IASO IVF Center
psath438@otenet.gr

Fifth baby born in Greece using the maternal spindle transfer method as part of pilot trial conducted by the Institute of Life and Embryotools scientific team

A fifth baby was born using the maternal spindle transfer method, as part of the pilot trial  conducted by the scientific team of the Institute of Life and Embryotools in Greece, on October 14, 2020, at IASO Hospital (Athens). In the context of this pilot trial, this method has already led to the birth of 4 more babies, from women with significant fertility problems and a serious history of multiple IVF failures.

The fifth baby was born to a 33 years old Greek mother, who had undergone nine failed IVF cycles in the past. Because of her poor oocytes quality, none of her fertilized oocytes reached the blastocyst stage.

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Our R&D centre receives support from CDTI to study new strategies to prevent prevalence of chromosomal abnormalities

The Embryotools R&D centre has received support from CDTI (Center for technological and industrial development) to carry out another innovative project with the aim to study new strategies to prevent or reduce the prevalence of chromosomal abnormalities at the early stages of the embryo development.

F15c_Diploma_2377_002_20-200907-CER-RD_001-B66034612

 

Strategies for oocyte rejuvenation: to what extent?

Infertility attributed to male and female factors affects millions of couples worldwide. Although assisted
reproductive technologies (ART) can circumvent some of these fertility problems, the efficacy of the treatments is greatly dependent on the quality of the oocytes used. Frequently, oocytes from patients of advanced age or with other fertility disorders (e.g, polycystic ovarian syndrome, endometriosis) fail to fertilize, produce embryos that arrest during the first stages of their development in vitro or develop into chromosomally abnormal blastocysts. The use of donated oocytes can represent an effective approach to
improve the chances of successful IVF treatment in these patients, however, the resultant children are not genetically related to the intended mothers and thus it desirable to develop other alternatives

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Fourth Baby Born in 14 Months Using the Maternal Spindle Transfer Method as Part of Pilot Trial Conducted by the Institute of Life and Embryotools Scientific Team

ATHENS, Greece, June 30, 2020 /PRNewswire/ — Within 14 months from the birth of the first baby, three more babies have been born using the maternal spindle transfer method, as part of the pilot trial conducted by the scientific team of the Institute of Life and Embryotools in Greece.

The fourth baby was born at 10:40 am on June 20, 2020, at IASO Hospital, to a Greek mother with a long history of multiple IVF failures. Both the mother and the infant are in very good health.

 

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Cryopreservation of oocytes and embryos in times of COVID-19: Can the cure be worse than the disease? Risk assessment in the IVF laboratory

 

Authors:

Nuno Costa-Borges, Ph.D.1, Mònica Acacio, M.Sc.1, Ivette Vanrell, M.Sc.1, Gloria Calderón, Ph.D.1

1Embryotools, Parc Cientific de Barcelona

Consider This:

Since the state of alarm was decreed in Spain due to the COVID-19 pandemic, we have gone through an initial skepticism phase that was then followed by the temporary cessation of all activities in the IVF laboratories, similarly to what happened in most European countries. During this period, the different national and international Scientific Societies have prepared guidelines with instructions for reproductive centers, which have been prepared on the basis of the available knowledge about the virus (1-3). These recommendations have been updated regularly and contributed to the evaluation of the possible risks of transmission of SARS-CoV-2 to reproductive cells and have helped IVF centers to implement preventive measures. Similarly, governmental agencies such as FDA in the US that regulate use of donor gametes or embryos provided additional guidance for cases where heterologous material is used (4). However, recommendations of additional screening and testing of donors has been quite minimal. Now that many centers are returning to normal activities, there are still doubts in regard to specific laboratory procedures. In particular, one of the most unsettled questions is the potential risk of cross-contamination with SARS-CoV-2 during cryopreservation procedures or the storage of the reproductive cells in liquid or vapor phase nitrogen tanks. In this regard, we consider that it is important to evaluate carefully the pros and cons of each of the measures proposed to avoid unnecessary risks.

Read more : https://www.fertstertdialog.com/posts/cryopreservation-of-oocytes-and-embryos-in-times-of-covid-19-can-the-cure-be-worse-than-the-disease-risk-assessment-in-the-ivf-laboratory?utm_source=user_mailer&utm_medium=email&utm_campaign=send_content_share_for_existing_user

 

Maternal spindle transfer overcomes embryo developmental arrest caused by ooplasmic defects in mice

Abstract

The developmental potential of early embryos is mainly dictated by the quality of the oocyte. Here, we explore the utility of the maternal spindle transfer (MST) technique as a reproductive approach to enhance oocyte developmental competence. Our proof-of-concept experiments show that replacement of the entire cytoplasm of oocytes from a sensitive mouse strain overcomes massive embryo developmental arrest characteristic of non-manipulated oocytes. Genetic analysis confirmed minimal carryover of mtDNA following MST. Resulting mice showed low heteroplasmy levels in multiple organs at adult age, normal histology and fertility. Mice were followed for five generations (F5), revealing that heteroplasmy was reduced in F2 mice and was undetectable in the subsequent generations. This pre-clinical model demonstrates the high efficiency and potential of the MST technique, not only to prevent the transmission of mtDNA mutations, but also as a new potential treatment for patients with certain forms of infertility refractory to current clinical strategies.

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First foal born in Spain using a procedure which enhances reproductive efficiency and genetic preservation in elite animals

 

 

 

 

 

 

First foal born in Spain using a procedure which enhances reproductive efficiency and genetic preservation in elite animals

• The first horse conceived as a result of a combination of ovum pick up (OPU) and intracytoplasmic sperm injection (ICSI), two in vitro fertilisation techniques which enhance fertility and enable the genetic preservation of elite animals, has just been born in Catalonia.
• This birth points to the future of equine assisted reproduction in Spain. It has been made possible by a project carried out entirely in the country led by the Embryotools centre based in the Barcelona Science Park in partnership with CREA Veterinaris and Embriones Equino.
• ICSI was developed in 1992 to treat men with fertility problems and is now a routine procedure in human assisted reproduction laboratories. Nonetheless, in horses there are very few laboratories (around five worldwide) that have achieved successful results.
• In 2009, the Embryotools team successfully cloned the first animals in Spain, while in 2012 the centre’s scientists were the first in Europe to achieve the birth of healthy horses after embryonic sex selection.

Barcelona, 2 June 2020. The Spanish Embryotools centre, which is based in the Barcelona Science Park (Parc Científic de Barcelona, PCB) and a pioneer in human and animal assisted reproduction, and CREA Veterinaris, which has over 25 years of experience in equine assisted reproduction, have achieved this first birth in Spain by combining ovum pick up (OPU) and intracytoplasmic sperm injection (ICSI). The foal was born on a farm in Viladrau, northern Catalonia, in the early hours of 22 May after 11 months of normal gestation.
This birth is a milestone in the future of equine assisted reproduction in Spain. It was made possible by a collaboration project between Embryotools and CREA Veterinaris in Taradell (Barcelona) along with the Seville-based firm Embriones Equinos, a leading provider of brood mares.
“ICSI first emerged in 1992 for treating men with fertility problems and is now a routine procedure in human assisted reproduction laboratories. Nonetheless, in horses there are still very few laboratories (around five worldwide) that have achieved successful results. Due to the specificity of the equine oocyte, we have had to modify the procedure and use a sperm microinjection system with a Piezo system in order to achieve better results while also adapting the in vitro culture system,” says Dr Gloria Calderón, Director of Embryotools.
The process posed other problems specific to the equine species. “The first is that the mares do not respond to superovulation treatments, so we cannot get several mature ova. The second is that ultrasound-guided retrieval of ova by OPU is not easy. Although the mare copes with this procedure very well, it calls for experienced veterinarians and a good deal of training,” points out Dr Guillem Formiguera, co-director of CREA Veterinaris.
“The ova were obtained at CREA Veterinaris’ reproduction centre in Viladrau in northern Catalonia. They were then sent to our laboratory where they were matured in vitro and fertilised by means of Piezo-ICSI. The resulting embryos were cultured for eight days and sent back to the farm to be transferred to the recipient mothers,” adds Dr Nuno Costa-Borges, Scientific Director at Embryotools.

A new era of assisted reproduction in horses

One of the great advantages of the OPU-ICSI technique is that only one sperm per ovum is needed. By contrast, in conventional insemination several million spermatozoa are required for one of them to get through the barriers of the ovum, penetrate it and generate an embryo.
Most mares have their reproductive cycle during the spring and summer (the breeding season) in the months of greatest light, and few are reproductively active during the winter. So as Dr Sara Valls, co-director of CREA Veterinaris, notes: “With this technique, reproductive cycles can be extended to times when mares do not habitually cycle and vitrified embryos can be saved for transfer at a later date, as is done with embryos resulting from in vivo insemination programmes.”
This technique also allows embryos to be obtained from mares with fertility problems, and instead of one embryo per cycle, up to five can be obtained per mare every 14 days. “Although we get a high level of efficiency with the transfer programme with embryos generated by in vivo insemination, we saw that with this technique we could get embryos from stallions or mares with fertility problems which we could not do with traditional methods. So we teamed up with Embryotools to deliver this service. ICSI is so efficient at present that it can even be used to produce healthy female embryos, thus maximising the use of semen,” says Dr Formiguera.
The method enhances genetic quality in stud farms because it makes it possible to get foals from the best mares while also avoiding gestation fatigue of mares taking part in equestrian competitions. The technique can be used with any equine breed. However, it will be most sought after by breeders of high genetic value horses who will now be able to use it in Spain and will no longer have to go abroad. This IVF procedure also has great potential in terms of improvement programmes for Spanish purebred horses and elite animals. These techniques are currently in use with demand growing year after year for breeding sports horses in Europe and, albeit to a lesser extent but also rising, for other types of breeds such as the Arabian purebred and quarter horse. Scientists think that this technique also has the potential to recover other wild or endangered species.

About Embryotools
With over 30 years of experience in clinical embryology and human and animal assisted reproduction, Embryotools is a leading centre in this field in the domestic and international market. It was founded by two scientists, Gloria Calderón and Nuno Costa-Borges, both embryologists, who are driven by innovation and excellence and are passionate about the continuous improvement of assisted reproduction techniques.
In 1984, Dr Calderón was a member of the team that achieved the first pregnancy by in vitro fertilisation in Spain, and in 2009, along with Dr Costa-Borges, of the team that first successfully cloned animals in Spain. Recently, in 2019, they achieved the birth of the world’s first baby using a mitochondrial replacement technique in oocytes with poor oocyte quality.
Embryotools’ operations are divided into four major business areas: Quality Control Services to test all types of materials, culture mediums and products used in IVF laboratories; a Training Centre for sharing its experience and knowledge with professionals seeking excellence; independent Scientific and Clinical Advice and Consultancy Services, and an Animal Reproduction Centre, where the most innovative techniques are used to improve the reproductive output of elite animals. ________________________________________________________________________________________ More information: Azucena Berea • Press Officer • Barcelona Science Park • Tel. (+34) 93 403 46 62 • aberea@pcb.ub.c

Patients recruiting phase for the clinical pilot trial on maternal spindle transfer conducted by Embryotools and the Institute of Life is now concluded

Embryotools and the Institute of Life communicate that a total of 25 patients have been successfully recruited to participate in the first registered pilot trial that is being conducted by Embryotools and the Institute of Life in Greece. The pilot trial has been approved in accordance to the terms and conditions of the Greek Law 3305/2005 and registered in a primary clinical trial registry (ISRCTN) recognized by WHO and ICMJE.

The 25 patients have been selected following the strict inclusion criteria defined in the framework of this clinical research project, which aims to evaluate the effectiveness and safety of the maternal spindle transfer technique as a means to treat infertility problems associated to cytoplasmic dysfunctions in oocytes – which manifest by a “massive” embryo development arrest in IVF cycles with conventional techniques – as well as to prevent the transmission of mitochondrial diseases.

Embryotools and the Institute of Life will like to express their gratefulness to all patients that contacted us and manifested their support and interest in participating in this project. The project is expected to be concluded within the next months and results will be made public after the acceptance of the publications in specialized peer-reviewed journals.

http://www.isrctn.com/ISRCTN11455145

 

Ensayan con éxito una nueva técnica para evitar transmisión de enfermedades
www.lavanguardia.com
BARCELONA, 07/11/2017 22:02 (EUROPA PRESS)La American Society for Reproductive Medicine (ASRM) ha premiado una investigación del centro Embryotools –con sede en el Parc Científic de Barcelona (PCB)– por la…

Barcelona, 25 oct (EFE).- El centro de investigación sobre embriones Embryotools, situado en el Parque Científico de Barcelona, ha finalizado con éxito los primeros ensayos de una innovadora técnica de reproducción asistida, denominada Transferencia de Huso Materno, que evita la transmisión de enfermedades mitocondriales.

La nueva técnica se engloba en las técnicas conocidas como de ‘tres padres’ (“three parents baby”), que científicos punteros de todo el mundo están estudiando para evitar la transmisión de enfermedades hereditarias.