ідея - Medical Research - # Male Infertility Treatment

Restoring Sperm Motility in Mice with Oligo-Astheno-Teratozoospermia Using mRNA Injection and Electroporation

Q: What ethical considerations should be taken into account when applying gene therapy or mRNA-based treatments for male infertility?

When considering the application of gene therapy or mRNA-based treatments for male infertility, several ethical considerations must be carefully addressed. Firstly, there is a need to ensure that the treatment is safe and effective, with minimal risks to both the individual receiving the treatment and any potential offspring. This involves thorough preclinical testing in animal models to assess efficacy and safety before moving on to human trials. Another crucial ethical consideration is informed consent. Patients must be fully informed about the nature of the treatment, including potential risks and benefits, as well as alternative options available to them. They should have a clear understanding of how their genetic information will be used and shared during the course of treatment. Furthermore, issues related to genetic modification raise complex ethical dilemmas. The permanence of genetic changes introduced through gene therapy requires careful consideration of long-term implications for both individuals and future generations. There are concerns about unintended consequences such as off-target effects or germline modifications that could impact not only the patient but also their descendants. Additionally, equitable access to these advanced treatments is essential from an ethical standpoint. Ensuring that these therapies are affordable and accessible to all individuals who could benefit from them helps prevent exacerbating existing health disparities based on socioeconomic status or geographic location. In summary, key ethical considerations in applying gene therapy or mRNA-based treatments for male infertility include safety, informed consent, genetic modification implications, and equitable access.

Q: How do the risks associated with conventional DNA plasmid vectors compare to those of naked mRNA injections?

Conventional DNA plasmid vectors used in gene therapy present certain risks that differ from those associated with naked mRNA injections. DNA plasmids have a higher risk profile due to their ability to integrate into the host genome upon transfection which can lead to insertional mutagenesis - where random integration may disrupt normal genes leading potentially harmful consequences like cancer development [9]. Additionally, since DNA plasmids persist within cells after transfection they pose a long-term risk compared with transient expression seen in RNA-based therapies [10]. On contrary Naked mRNA injections offer some advantages over traditional DNA plasmid vectors by avoiding genomic integration altogether making it safer option especially when heritable alterations are undesirable[11]. Since mRNAs do not alter host genome they eliminate concerns regarding permanent changes being passed onto future generations thus reducing overall risk profile significantly[12]. While both approaches carry inherent risks such as immune responses against exogenous nucleic acids (mRNA) or possible inflammatory reactions at injection sites (plasmids), it's evident that naked mRNA injections provide a safer alternative by eliminating genomic integration-related hazards typically associated with conventional DNA plasmid vectors.

Q: How might advancements in genetic research impact future treatments for male infertility?

Advancements in genetic research hold significant promise for revolutionizing future treatments for male infertility by offering more precise diagnostic tools and targeted therapeutic interventions tailored towards underlying molecular causes contributing towards reproductive disorders. 1- Precision Medicine: Genetic research enables identification of specific mutations linked with male infertility allowing personalized diagnosis & management strategies based on individual's unique genetic makeup rather than one-size-fits-all approach improving outcomes significantly 2- Gene Editing Technologies: Innovations like CRISPR-Cas9 offer new avenues for correcting disease-causing mutations directly within germ cells providing hope for treating inheritable forms of male infertility effectively while minimizing transmission risk 3- Stem Cell Therapies: Research into stem cell biology has opened up possibilities around generating functional sperm cells from pluripotent stem cells paving way towards novel regenerative medicine approaches aimed at restoring fertility among infertile males 4- Epigenetic Modifications: Understanding epigenetic factors influencing spermatogenesis offers insights into reversible mechanisms affecting fertility enabling development targeted epigenetic therapies addressing aberrant methylation patterns impacting sperm quality 5- Non-Invasive Assisted Reproductive Techniques: Advances in non-invasive ARTs utilizing microfluidics technology combined with genomics data allow improved selection viable sperm enhancing success rates IVF procedures benefiting couples struggling conceive due severe male factor infertility

Основні поняття

The author demonstrates that the use of naked mRNA combined with electroporation efficiently restores spermatogenesis in mice suffering from oligo-astheno-teratozoospermia, offering a promising treatment for male infertility.

Анотація

The study focuses on restoring sperm motility in mice with oligo-astheno-teratozoospermia using mRNA injection and electroporation. The research highlights the importance of genetic factors in male infertility and presents a novel approach to treat this condition. By comparing the efficacy of mRNA and DNA vectors, the study shows that naked mRNA can successfully restore spermatogenesis without the risks associated with gene therapy. The results indicate that mRNA injection combined with electroporation leads to the presence of normal and motile sperm in infertile mice, opening new possibilities for male infertility treatment.

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biorxiv.org

Статистика

Patients and mice bearing mutations in the ARMC2 gene have decreased sperm concentration.
Intra Cellular Sperm Injection (ICSI) has limited efficacy for treating conditions like OAT.
mRNAs coding for reporter genes are detected for up to 3 weeks mostly in germ cells.
Injection and electroporation of naked mRNA-Armc2 into testes restored spermatogenesis.
EEV shows low and transient expression in spermatogenic cells.

Цитати

"The study shows for the first time that mRNA-Armc2 efficiently restores spermatogenesis."
"Patients with severe infertility can only conceive through assisted reproductive technologies like ICSI."
"Gene therapy cannot be used to treat infertility due to ethical reasons and potential biological risks."

Ключові висновки, отримані з

Sperm motility in mice with Oligo-astheno-teratozoospermia restored by in vivo injection and electroporation of naked mRNA

by Vilpreux,C.,... о www.biorxiv.org 12-14-2023

https://www.biorxiv.org/content/10.1101/2023.12.12.571239v1

Глибші Запити

What ethical considerations should be taken into account when applying gene therapy or mRNA-based treatments for male infertility?

When considering the application of gene therapy or mRNA-based treatments for male infertility, several ethical considerations must be carefully addressed. Firstly, there is a need to ensure that the treatment is safe and effective, with minimal risks to both the individual receiving the treatment and any potential offspring. This involves thorough preclinical testing in animal models to assess efficacy and safety before moving on to human trials.
Another crucial ethical consideration is informed consent. Patients must be fully informed about the nature of the treatment, including potential risks and benefits, as well as alternative options available to them. They should have a clear understanding of how their genetic information will be used and shared during the course of treatment.
Furthermore, issues related to genetic modification raise complex ethical dilemmas. The permanence of genetic changes introduced through gene therapy requires careful consideration of long-term implications for both individuals and future generations. There are concerns about unintended consequences such as off-target effects or germline modifications that could impact not only the patient but also their descendants.
Additionally, equitable access to these advanced treatments is essential from an ethical standpoint. Ensuring that these therapies are affordable and accessible to all individuals who could benefit from them helps prevent exacerbating existing health disparities based on socioeconomic status or geographic location.
In summary, key ethical considerations in applying gene therapy or mRNA-based treatments for male infertility include safety, informed consent, genetic modification implications, and equitable access.

How do the risks associated with conventional DNA plasmid vectors compare to those of naked mRNA injections?

Conventional DNA plasmid vectors used in gene therapy present certain risks that differ from those associated with naked mRNA injections.
DNA plasmids have a higher risk profile due to their ability to integrate into the host genome upon transfection which can lead to insertional mutagenesis - where random integration may disrupt normal genes leading potentially harmful consequences like cancer development [9]. Additionally, since DNA plasmids persist within cells after transfection they pose a long-term risk compared with transient expression seen in RNA-based therapies [10].
On contrary Naked mRNA injections offer some advantages over traditional DNA plasmid vectors by avoiding genomic integration altogether making it safer option especially when heritable alterations are undesirable[11]. Since mRNAs do not alter host genome they eliminate concerns regarding permanent changes being passed onto future generations thus reducing overall risk profile significantly[12].
While both approaches carry inherent risks such as immune responses against exogenous nucleic acids (mRNA) or possible inflammatory reactions at injection sites (plasmids), it's evident that naked mRNA injections provide a safer alternative by eliminating genomic integration-related hazards typically associated with conventional DNA plasmid vectors.

How might advancements in genetic research impact future treatments for male infertility?

Advancements in genetic research hold significant promise for revolutionizing future treatments for male infertility by offering more precise diagnostic tools and targeted therapeutic interventions tailored towards underlying molecular causes contributing towards reproductive disorders.
1- Precision Medicine: Genetic research enables identification of specific mutations linked with male infertility allowing personalized diagnosis & management strategies based on individual's unique genetic makeup rather than one-size-fits-all approach improving outcomes significantly
2- Gene Editing Technologies: Innovations like CRISPR-Cas9 offer new avenues for correcting disease-causing mutations directly within germ cells providing hope for treating inheritable forms of male infertility effectively while minimizing transmission risk
3- Stem Cell Therapies: Research into stem cell biology has opened up possibilities around generating functional sperm cells from pluripotent stem cells paving way towards novel regenerative medicine approaches aimed at restoring fertility among infertile males
4- Epigenetic Modifications: Understanding epigenetic factors influencing spermatogenesis offers insights into reversible mechanisms affecting fertility enabling development targeted epigenetic therapies addressing aberrant methylation patterns impacting sperm quality
5- Non-Invasive Assisted Reproductive Techniques: Advances in non-invasive ARTs utilizing microfluidics technology combined with genomics data allow improved selection viable sperm enhancing success rates IVF procedures benefiting couples struggling conceive due severe male factor infertility