Targeted delivery to the central nervous system improves motor function and prolongs lifespan in primates and mice.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused primarily by mutations in the gene MeCP2 (Methyl-CpG-binding protein 2), characterized by acquired speech loss, hand stereotypies, and gait abnormalities that appear after a period of apparently normal postnatal development. It primarily affects girls, with an incidence of approximately 1 in 10,000 births, and is present in a wide range of racial and ethnic groups worldwide.

RTT, like other neurological conditions, represents a significant challenge for physicians in terms of treatment and medication administration. Our brain is a very demanding organ when it comes to what it lets into its interior. It is protected by the blood-brain barrier, which filters and regulates the flow of blood through brain tissue and only allows certain molecules to enter and exit our brain, while keeping harmful substances, such as germs, out.

Since 2016, thanks to a team of researchers from the School of Veterinary Medicine at the University of Pennsylvania, it is known that unlike most pathogens, Toxoplasma gondii It can cross the blood-brain barrier and invade cells, passing directly from the blood into endothelial cells, replicating inside them, causing them to rupture and then infecting nearby brain cells.

The Toxoplasma gondii It is an intracellular protozoan parasite that causes toxoplasmosis, a disease that can range from mild to severe depending on the host's immune status. It is estimated that one-third (25%-35%) of the world's human population is infected and can survive in the central nervous system for the rest of our lives without causing health problems. 

In 2024 a group of neuroscientists have conducted research on the Toxoplasma gondii, a parasite that naturally travels from the human gut to the central nervous system (CNS) by its ability to cross the blood-brain barrier, as a potential biological tool that can be harnessed constructively to transport and deliver drugs into our brains.

Researchers genetically modified the system used by the Toxoplasma gondii To secrete the hybrid protein, the parasite has two secretory organelles, which were chosen to deliver the proteins to neurons. The proteins located in these organelles were fused with a protein called MeCP2 in neurons cultured in a Petri dish. After being "enhanced," it was injected into mice to observe its pathway and evaluate the effects produced in the brains of mice infected with the modified Toxoplasma.

The researchers managed to Toxoplasma gondii Transport therapeutic proteins into the host's neurons, crossing the brain-brain barrier that normally prevents the passage of other drugs or compounds. Upon reaching the mice's brains, the parasite binds to the DNA of their brain cells and manages to alter host gene expression in the cells and organoids of their neurons and brain. Furthermore, the researchers observed that the entire operation occurred without significant inflammation after delivery of the MeCP2 hybrid protein.

This research work has been published in Nature Microbiology, although it is in its preliminary stage and more research is needed to understand the possible limitations, including efficacy and safety, it is encouraging that through an alternative approach to therapeutic protein delivery, currently incurable neurological diseases such as RTT, Alzheimer's or Parkinson's could be treated.

The role of the MeCP2 protein in the brain

The MeCP2 protein acts as a master gene regulator in the brain, helping to activate or silence specific genes based on the needs of neuronal cells, but it is crucial to recognize that the protein is also expressed in numerous non-neural tissues, including the lung. 

The MeCP2 protein was first described in 1992, but was only accepted by the scientific community in 1999 when Ruth Amir and Huda Zoghbi established its connection with Rett syndrome, demonstrating that mutations in this protein are the genetic cause of the 95% in RTT cases.

A progressive neurodevelopmental disorder and one of the most common causes of cognitive disability in females, it is characterized by developmental regression, motor dysfunction, midline hand stereotypies, autonomic nervous system dysfunction, epilepsy, scoliosis, and autism-like behavior.

In males, however, mutations in MeCP2 can lead to a wide spectrum of clinical presentations ranging from mild intellectual impairment to severe neonatal encephalopathy and premature death.

Another rare MeCP2-driven neurodevelopmental disorder with symptoms that overlap with RTT is MeCP2 duplication syndrome (MDS). MDS is found primarily in males. The duplication is typically inherited from an apparently asymptomatic carrier mother and presents with developmental delay, hypotonia, autistic features, refractory epilepsy, and recurrent respiratory infections. 

Mutations causing RTT and related neurological disorders have been identified throughout the MeCP2 locus, but the effects vary depending on the type of mutation and location.

Given the functional importance and elevated presence of MeCP2 in the brain, it is not surprising that alterations in this protein not only influence the development of Rett syndrome, but also have a pleiotropic effect, being linked to various psychological disorders such as depression, autism, schizophrenia, and epilepsy.

Clinical presentation of Rett syndrome (RTT)

Rett syndrome was first described by Dr. Andreas Rett in 1966, where he described 22 girls, each with an uncomplicated birth history and typical development until approximately 1 year of age. However, at that age, Rett observed that the girls showed a consistent pattern of disruption in their typical development. In 1983, neurologist Bengt Hagberg and his team presented an analysis of 35 cases that showed “developmental arrest… accompanied by accelerated deterioration of higher brain functions” in girls from France, Portugal, and Sweden. 

Identifying similarities with the cases detailed in Rett's 1966 report, Hagberg named this set of clinical features Rett syndrome.

Missense mutations in the methyl-binding domain or the methyl-binding domain repressor transcription of MeCP2 are sufficient to cause RTT.

With his extensive experience, Hagberg proposed a four-stage system that describes the temporal progression of the disease: (1) early onset, (2) regression, (3) plateau, and (4) late motor deterioration.

The first stage, Known as early onset, it is characterized by development that appears relatively normal, although subtle signs of delayed progression of psychomotor skills (developmental delay) and growth may appear, specifically, a decrease in the rate of growth of the head circumference.

The second stage, which occurs between 6 and 18 months of age, is characterized by a partial or complete loss of previously acquired skills, such as spoken language and manual dexterity. During this phase, repetitive hand movements, such as wringing/clenching, also emerge, as well as difficulty walking or even an inability to walk. During this period, some children with RTT may experience respiratory problems, such as hyperventilation or apnea, although these usually manifest most frequently during the plateau stage.

The regression phase can last for several months or even years, after which those affected usually progress to the plateau stage between 3 and 5 years of age.

The third stage, referred to as a plateau, occurs as a period of stability in the phenotype because there is no further loss of skills and behavioral and cognitive function may stabilize, while other medical conditions become apparent, such as seizures, gastrointestinal and nutritional problems (particularly constipation), other movement disorders, autonomic abnormalities, and other medical problems.

Finally, the fourth stage Corresponds to late motor deterioration, people with RTT may experience decreased mobility, the appearance of parkinsonian features and scoliosis, leading to significant motor disability and, in some cases, loss of the ability to ambulate.

It is important to note that this staging system is a general characterization of clinical progression and that not all girls with RTT will experience every stage or every clinical feature.

Clinical presentation of MeCP2 duplication syndrome

In 1999, Lubs and colleagues carried out a linkage study in a family of five males with intellectual and developmental disabilities, managing to locate the responsible gene in the Xq28 region of the X chromosome. It was not until 20025 that MeCP2 was identified as the gene causing the X-linked intellectual development disorder.

MDS primarily affects males and is characterized by a wide variety of symptoms, but its most common features include developmental delay or intellectual disability ranging from severe to profound, hypotonia, autistic features, epilepsy, progressive spasticity of the lower limbs, impaired speech development, recurrent infections, and gastrointestinal problems.

The breakthrough: MeCP2 protein supplementation

Protein delivery faces complex challenges: overcoming the biological barriers that separate the delivery site from the target cells, and preserving the integrity of the protein until it reaches its final destination. Many proteins require precise targeting to specific tissues, cell types, or intracellular compartments to be effective, otherwise they may be ineffective or even harmful. 

Recently, pioneering research has opened up the possibility of treating Rett Syndrome through direct supplementation of the MeCP2 protein. This therapeutic approach seeks to compensate for the lack of functionality of the protein produced by the affected cells, partially restoring neuronal function.

The study, published in Nature, showed that administering a modified version of the MeCP2 protein to animal models with Rett resulted in significant improvements in motor and cognitive behavior. This treatment uses a delivery system that allows the protein to cross the blood-brain barrier, a major challenge in neurological diseases.

The development of new genetic tools has made it possible to identify the genetic basis of numerous intellectual and developmental disabilities. This opens up exciting possibilities for research and the design of gene therapy treatments for genetic disorders.

What does this treatment mean for families?

Although this approach is in the early stages of research, it represents hope for thousands of families. Unlike current therapies, which only treat symptoms, MeCP2 supplementation could address the underlying cause of the syndrome. However, significant challenges remain, such as:

• Associated risksExcess MeCP2 can be toxic, so treatment must be carefully adjusted.
• Long-term security: It is crucial to evaluate side effects in larger clinical studies.

The future of treatment for Rett Syndrome

The administration of the MeCP2 protein not only offers hope for people affected by Rett syndrome, but also advances research into other genetic diseases. This breakthrough demonstrates how biotechnology and precision medicine can transform lives.

For families facing the challenges of Rett Syndrome, staying informed and connected with specialists and support groups is critical. This discovery underscores the importance of investing in science to offer innovative solutions to previously untreatable diseases.

At Enevia we offer specialized consulting services and different tests that can guide you in different areas such as neurology, genetics, nutrition and general medicine, as well as help you make the right decisions and analyze medical tests to achieve effective treatment for the pathologies that you may suffer from.

Enter our website through www.eneviacare.com and you will be able to find the services that we can offer you.

Also, you can visit our website www.eneviahealth.com and see the tests we offer.

At Enevia, we are your ally in health!

Article written by Enevia Health Advisor and Collaborator:

Yohana Cespedes, Chemical Eng.

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