What is Mitochondrial Replacement Therapy? Know it all

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What is Mitochondrial Replacement Therapy?

Mitochondrial Replacement Therapy (MRT) is a cutting-edge medical technique designed to prevent the transmission of mitochondrial diseases from mother to child. These diseases are caused by mutations in mitochondrial DNA (mtDNA), which can lead to severe, often fatal, health conditions. MRT involves replacing defective mitochondria in a mother’s egg with healthy mitochondria from a donor, thereby allowing the birth of a child free from mitochondrial disease. This article provides a comprehensive overview of MRT, from the role of mitochondria in cells to the intricacies of the therapy itself.

What are Mitochondria?

Mitochondria are small, double-membrane-bound organelles found in the cytoplasm of almost all eukaryotic cells. Often referred to as the “powerhouses of the cell,” their primary function is to produce adenosine triphosphate (ATP), the energy currency of the cell, through a process known as oxidative phosphorylation. This process is critical for cell survival and function.

Structure and Function

Each mitochondrion has its own set of DNA (mtDNA), which is distinct from the nuclear DNA. This mtDNA encodes for proteins essential to the mitochondrion’s energy-producing functions. Mitochondria also play roles in other cellular processes such as:

• Regulation of the Cell Cycle and Growth: Mitochondria influence the regulation of the cell cycle and apoptosis (programmed cell death).
• Calcium Storage and Signaling: They act as reservoirs for calcium ions, which are critical for various cellular functions.
• Heat Production: In brown fat cells, mitochondria generate heat through non-shivering thermogenesis.
• Metabolism of Reactive Oxygen Species: They help in detoxifying reactive oxygen species (ROS), which can damage cells if not properly managed.

Mitochondrial Inheritance

Mitochondria are maternally inherited, meaning all of an individual’s mitochondria are derived from their mother. This inheritance pattern makes the mtDNA susceptible to mutations that can be passed from mother to child, potentially leading to mitochondrial diseases.

What is MRT?

Mitochondrial Replacement Therapy is a reproductive technology that allows the replacement of defective mitochondria in an egg or embryo with healthy mitochondria from a donor. The goal is to prevent the transmission of mitochondrial diseases, which can cause severe health problems and are currently incurable.

Purpose of MRT

The primary purpose of Mitochondrial Replacement Therapy is to enable women with mitochondrial DNA mutations to have biological children without passing on these mutations. By replacing defective mitochondria, MRT aims to give these children a chance for a healthier life, free from mitochondrial disease. The procedure is especially pertinent for families with a history of mitochondrial disorders and is seen as a beacon of hope for reducing the burden of these debilitating conditions.

MRT helps in treating or preventing the following mitochondrial disorders:

• Leigh Syndrome: A severe neurological disorder that typically arises in infancy, leading to progressive loss of mental and movement abilities, and often resulting in early death.
• Mitochondrial Myopathy: A group of disorders causing muscle weakness and fatigue due to defects in mitochondrial function, often impacting muscle fibers and leading to exercise intolerance and other systemic issues.
• MELAS Syndrome: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, a disorder that affects many of the body’s systems, particularly the brain and muscles, causing stroke-like episodes, muscle weakness, and other neurological issues.
• MERRF Syndrome: Myoclonic Epilepsy with Ragged Red Fibers, characterized by muscle twitches (myoclonus), epilepsy, and progressive stiffness (spasticity), often affecting movement and coordination.
• NARP Syndrome: Neuropathy, Ataxia, and Retinitis Pigmentosa, a condition that causes sensory neuropathy, balance problems, and vision loss due to degeneration of the retina.
• Kearns-Sayre Syndrome: A neuromuscular disorder with onset before age 20, leading to progressive external ophthalmoplegia (weakness of the eye muscles) and pigmentary retinopathy, often accompanied by heart block and muscle weakness.
• Chronic Progressive External Ophthalmoplegia (CPEO): A condition that primarily affects the muscles controlling eye and eyelid movement, leading to drooping eyelids (ptosis) and limited eye movement.
• Pearson Syndrome: A rare, often fatal disorder that affects the bone marrow and pancreas, causing anemia, low white blood cell and platelet counts, and metabolic issues in infancy.
• Leber’s Hereditary Optic Neuropathy (LHON): A genetic disorder causing sudden, acute loss of vision, typically in young adulthood, due to degeneration of retinal ganglion cells.
• Barth Syndrome: A rare X-linked disorder that primarily affects males, leading to cardiomyopathy, neutropenia (low white blood cells), skeletal muscle weakness, and growth delay.
• Mitochondrial DNA Depletion Syndromes (MDDS): A group of conditions that result in a significant reduction of mitochondrial DNA, leading to severe muscular and neurological symptoms and often early death.
• Hereditary Spastic Paraplegia (HSP): A group of inherited disorders characterized by progressive weakness and spasticity of the lower limbs, often linked to defects in mitochondrial function.
• Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A disorder that causes severe gastrointestinal dysmotility, peripheral neuropathy, and neurological issues due to defective mitochondrial DNA maintenance.( Know more about- What is Cost of IVF in Mumbai? )

Types of MRT

Pronuclear Transfer (PNT)

In Pronuclear Transfer, two embryos are created: one from the mother’s egg and father’s sperm, and another from a donor’s egg and father’s sperm. Before the embryos begin dividing, the pronuclei (the genetic material from the mother and father) are removed from the mother’s embryo and transplanted into the donor embryo, which has had its pronuclei removed. This newly constructed embryo now contains the nuclear DNA from the mother and father, and healthy mitochondria from the donor.

Maternal Spindle Transfer (MST)

Maternal Spindle Transfer involves transferring the mother’s nuclear DNA to a donor egg that has had its own nuclear DNA removed but retains healthy mitochondria. This reconstructed egg is then fertilized with the father’s sperm. MST is performed before fertilization, unlike PNT, which occurs after fertilization but before the embryo begins dividing.

Polar Body Transfer (PBT)

This method involves transferring a polar body containing the mother’s mitochondrial DNA to a donor egg. Polar bodies are by-products of oocyte development that contain excess genetic material. PBT is less common and is still largely experimental.

Diagnostic Procedures

Genetic Testing and Counseling

Before considering MRT, families typically undergo genetic testing and counseling to confirm the presence and risks associated with mitochondrial DNA mutations. This process includes:

• Family History Analysis: Evaluating the family history of mitochondrial diseases.
• Genetic Screening: Using techniques like mitochondrial DNA sequencing to identify mutations.
• Consultation: Genetic counselors explain the risks, benefits, and ethical considerations of Mitochondrial Replacement Therapy.

Pre-implantation Genetic Diagnosis (PGD)

PGD is a procedure used alongside IVF to screen embryos for mitochondrial mutations before implantation. This ensures that only embryos with healthy mitochondria are selected for the Mitochondrial Replacement Therapy process.

Preparation for MRT

Hormonal Stimulation and Egg Retrieval

The mother undergoes hormonal stimulation to induce the production of multiple eggs. These eggs are then retrieved in a process similar to standard IVF procedures. The egg donor also undergoes a similar process to provide healthy mitochondria.

Sperm Collection

The father’s sperm is collected and prepared for fertilization. In some cases, sperm from a donor may be used, depending on the specific circumstances and genetic risks.

Ethical and Legal Considerations

MRT raises significant ethical and legal questions, including concerns about genetic modification, the implications of three-parent DNA, and the potential long-term effects on the child. Families and medical practitioners must navigate these considerations carefully, often under the guidance of ethics boards and regulatory frameworks specific to their country.

The Procedure of MRT

Step-by-Step Process

Egg Collection: Eggs are collected from both the mother and the donor after hormonal stimulation.

Nuclear Transfer:

In MST, the mother’s nuclear DNA is transferred to the donor egg before fertilization.

In PNT, the pronuclei are transferred from the mother’s embryo to the donor embryo after fertilization.

Fertilization: The reconstructed egg or embryo is fertilized with the father’s sperm if not already done.

Embryo Culture: The fertilized egg is cultured to develop into a healthy embryo.

Embryo Transfer: The healthy embryo is transferred to the mother’s uterus for implantation and subsequent pregnancy.

Aftercare

Monitoring Pregnancy

After the embryo transfer, the pregnancy is monitored closely with regular ultrasounds and health checks to ensure the developing fetus is healthy and there are no complications.

Post-birth Monitoring

Children born through Mitochondrial Replacement Therapy are monitored for mitochondrial function and overall health. This includes regular check-ups and possibly more detailed assessments to track their development and detect any signs of mitochondrial dysfunction early.

Long-term Follow-up

Given the novel nature of MRT, long-term follow-up studies are crucial to understanding the full implications of the therapy. This helps in assessing the health and development of children born through MRT and in refining the procedure for future use.

Risks and Considerations

Technical Risks

• Incomplete Removal of Mutated mtDNA: If the transfer process does not completely remove the defective mitochondria, there could be residual mitochondrial DNA mutations.
• Developmental Risks: There may be unforeseen effects on the embryo’s development due to the manipulation and transfer process.

Ethical and Social Concerns

• Three-Parent Children: The child will have genetic material from three people, raising questions about identity and parenthood.
• Genetic Modification: MRT borders on germline modification, which has broader ethical implications for future generations.

Regulatory and Legal Risks

Different countries have varying regulations concerning MRT. In some places, it is approved and regulated, while in others it is banned or under strict legal scrutiny.

Conclusion

Mitochondrial Replacement Therapy represents a revolutionary advance in reproductive medicine, offering hope to families affected by mitochondrial diseases. While it holds immense potential for preventing these debilitating conditions, it also poses significant technical, ethical, and regulatory challenges. 

As research progresses and more children are born through MRT, a deeper understanding of its long-term effects and societal implications will emerge, guiding its future use in medicine. Know more about MRT at best hospitals in Mumbai like Jaslok Hospital Mumbai.