Clinical Research on Autism Spectrum Disorder, Treatments, Causes and Symptoms
Autism spectrum disorder (ASD) is a complex neurological and behavioral condition that affects a person’s social interaction, communication, interests and behavior. ASD includes a wide range of symptoms and severity levels, making each individual situation unique.
Pathogenesis of autism
The mechanism of autism development is currently not well understood. Its different forms have their own characteristics of pathogenesis.
In general, there are several critical periods in a child’s development during which the most intense neurophysiological changes in the brain occur: 14-15 months, 5-7 years, 10-11 years. Pathological processes that fall within critical periods lead to developmental disorders.
With endogenous (caused by internal factors) childhood autism, the development of the child’s psyche in the early stages occurs asynchronously. This manifests itself in a violation of the sequence of motor, speech, and emotional maturation. During the normal development of a child, more complex mental functions one by one replace simpler ones. In the case of autism, there is an “interlayering” of simple functions with complex ones, for example, babbling appears after one year along with simple words.
The pathogenesis of autism-like syndrome with chromosomal abnormalities, metabolic disorders, organic brain damage may be associated with damage to certain brain structures.
In some cases, the maturation and restructuring of cells in the cerebral cortex, hippocampus and basal ganglia are disrupted.
Computed tomography images of children with ASD reveal changes in the cerebellum, brain stem, frontal cortex, and expansion of the lateral ventricles.
Evidence of impaired dopamine metabolism in the brain in autism is provided by data from positron tomography studies and hypersensitivity of dopamine receptors in the brain structures of children with autism in some of its forms.
Causes of Autism Spectrum Disorders
The causes of the development of autism spectrum disorders (ASD) are still not fully understood. Since the 1970s, many theories have emerged to explain the origin of autism. Some of them, for example, the “cold mother” theory, were subsequently refuted.
In the modern view, ASD is a polyetiological disease, that is, its development is associated with a combination of various factors. The main reasons include:
Genetic factors
Recent studies in Russia and abroad are actively studying the genes responsible for the occurrence of ASD. According to recent data, about half of these genes are widely distributed in the population, but the manifestation of the disease depends on their interaction and the influence of environmental factors.
Structural and functional brain disorders
With the advent of magnetic resonance imaging (MRI), it has become possible to study the brain in detail. People with ASD show changes in the structure of various brain structures, such as the frontal lobes, cerebellum, limbic system and brainstem. Changes in brain size have also been noted in children with ASD compared to healthy children: at birth it is reduced, but then increases sharply during the first year of life. Poor blood supply to the brain and cases of epilepsy also often accompany autism.
Biochemical changes
Numerous studies have been devoted to the study of brain metabolic disorders involved in the transmission of nerve impulses. For example, a third of children with ASD have elevated levels of serotonin in the blood. Other studies have shown elevated levels of glutamate and aspartate in all children with autism. There is a hypothesis that autism is associated with impaired absorption of certain proteins, such as gluten and casein, and research in this direction continues.
Denial of the vaccination myth
The popular myth linking autism to vaccinations is untrue. A study suggesting a link between measles vaccinations and the development of autism was published in the late 1990s in the Lancet journal. However, 10 years later it turned out that the study data were falsified, and the article was retracted after legal proceedings.
As a result, modern science continues to explore the many factors that may contribute to the development of ASD, recognizing the complexity and diversity of causes of this condition.
Main characteristics of ASD
Social interaction
People with ASD often have difficulty in social interactions. This may manifest as a lack of awareness of social cues such as facial expressions, gestures and voice intonation. They may have difficulty forming and maintaining friendships, preferring to be alone, or may be uncomfortable in social situations.
Communication
Communication difficulties in ASD can range from complete lack of speech to difficulty holding a conversation. Some people may use unusual speech patterns, such as echolalia (repetition of words or phrases). Others may have a rich vocabulary but not understand how to use language correctly in social contexts.
Behavior and interests
Stereotyped or repetitive movements such as rocking or flapping of arms are common. People with ASD may have limited and intense interests that occupy a significant amount of their time and attention. They may experience significant distress when their routine or environment changes.
Causes and risk factors
The causes of ASD are not fully understood, but the condition is believed to be caused by a complex interaction of genetic and environmental factors. Research suggests that inherited genetic mutations may play a significant role in ASD. In addition, environmental factors during pregnancy and early childhood may also contribute to the development of the disorder.
Diagnosis and treatment
Diagnosis of ASD is usually made through observations of the child’s behavior and interviews with parents and teachers. There are several diagnostic tools, such as ADOS (Schedule of Autism Diagnostic Observation) and ADI-R (Revised Autism Diagnostic Interview), that help professionals make a diagnosis.
Treatment approaches
Although there are currently no known treatments that can completely cure ASD, there are many therapeutic approaches that can help improve the quality of life for people with the disorder.
Regenerative medicine as a promising direction
In recent years, regenerative medicine has become one of the most promising areas in the study and treatment of ASD. Regenerative medicine focuses on repairing or replacing damaged cells, tissues, and organs using a variety of techniques, including stem cells, biomaterials, and biologically active molecules.
Stem cells
Research has shown that stem cells have the potential to repair damaged neurons and improve neural plasticity. Stem cell therapy may improve cognitive function and reduce behavioral symptoms in people with ASD. However, this method is still in the clinical trial stage, and further research is needed to confirm its effectiveness and safety.
Biomaterials and molecules of biological activity
Another promising approach is the use of biomaterials and molecules that can stimulate tissue regeneration and improve neural connections. These techniques may help restore brain functions impaired in ASD and improve behavior and cognition.
Phase II clinical trial of the safety and effectiveness of intravenous cord blood infusion for the treatment of children with autism spectrum disorders
Researchers from Duke University in the US completed an open-label phase 1 safety and tolerability study in 25 children diagnosed with ASD who received autologous umbilical cord blood (UCB) and were followed for a year ( NCT02176317 ). UCB was administered as a single infusion without prior immunosuppression. The safety and tolerability profile of autologous UCB infusion in ASD was excellent. Improvements in social communication abilities were noted on the caregiver-administered Vineland II Adaptive Behavior Scales and the Pervasive Developmental Disorders Inventory (PDDBI). The clinician-administered Global Clinical Impression Improvement Scale reflected positive changes in core ASD symptoms during the 6-month post-infusion period in approximately 60% of participants, as reflected by improvements in social communication skills, receptive/expressive language, reductions in repetitive behaviors, and decreases in sensory sensitivity. . The same group continued a double-blind, randomized phase 2 trial (NCT02847182) to evaluate the safety and effectiveness of UCB compared to placebo in improving social communication abilities. Children included in the study received a single intravenous infusion of autologous (n=56) or allogeneic (n=63) UCB or placebo (n=61).The infusions were well tolerated and patients were assessed 6 months after the procedure. The results showed no evidence of improvement in social communication or other autism symptoms. However, in the subgroup of children without intellectual deficits, those receiving UCB showed significant improvements in communication skills, exploratory measures (attention to toys and sustained attention), and increases in alpha and beta electroencephalographic power.
In general, autism is an impaired perception of external stimuli associated with hyperactivity of the brain, due to which a person does not have time to connect and analyze everything that he sees, hears and feels. Such perception causes the child to react sharply to some phenomena of the external world and hardly notice others, leads to difficulties in communicating with people, forms stable everyday habits, makes it difficult to adapt to new conditions, and prevents him from learning on an equal basis with peers (including through imitation of others).
Due to the peculiarities of perception, the human voice for people with autism is no different from other sounds; they react completely differently to any touch, even when it comes to clothing. And the more different stimuli, the stronger the irritation: for example, due to the simultaneous strong desire to go to the toilet, loud sounds and unpleasant touches, a child may develop panic. And repeated movements calm him down and help him feel safe.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by problems in social communication and interaction, as well as the presence of repetitive behaviors, interests and activities. ASD includes conditions such as classic autism, Asperger’s syndrome and other pervasive developmental disorders.
Symptoms of ASD
Problems in social communication: Difficulty establishing and maintaining relationships.
Difficulties in understanding and using non-verbal communication means (gestures, facial expressions).
Lack of social-emotional reciprocity (e.g., does not share emotions, does not respond to the emotions of others).
Repetitive behavior and narrow interests: Stereotypical or repetitive movements (flapping arms, rocking).
Rigidity in routine and rituals.
Narrow and intense interests (for example, a passion for only one topic or subject).
Unusual reactions to sensory stimuli (increased or decreased sensitivity to sounds, light, textures).
What are exosomes from mesenchymal stem cells
Exosomes are extracellular vesicles ranging in size from 30 to 150 nm that are secreted by various types of cells, including mesenchymal stem cells (MSCs). They contain proteins, lipids, mRNA, microRNA and other molecules that can influence the function of target cells.
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into various cell types, such as osteoblasts, chondrocytes, and adipocytes. MSCs have immunomodulatory and regenerative properties, which makes them promising for cell therapy.
Advantages of exosomes from MSCs:
Safety:
Exosomes are not capable of proliferation, which reduces the risk of tumor formation compared to using MSCs themselves.
They do not cause an immune response because they do not contain nuclear material.
Therapeutic potential:
MSC exosomes contain bioactive molecules that can stimulate tissue regeneration, reduce inflammation and promote wound healing.
They can transmit molecules that promote tissue repair and protection.
Transport and stability:
Exosomes are stable in biological fluids and can easily penetrate tissues, making them convenient for the delivery of therapeutic agents.
They can be easily collected, cleaned and stored, facilitating their use in clinical practice.
Exosome research
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by three core symptoms, which include social interaction deficits, cognitive dysfunction, and communication impairments. Over the past few years, their numbers have been steadily increasing without effective treatment. Using BTBR T+tf/J (BTBR) mice, which are a well-established model for assessing autism-like behavior because they include a behavioral phenotype consistent with human ASD (restricted social approach, low reciprocal social interactions, and impaired childhood play), Peters and colleagues demonstrated that intranasal administration of MSC-Exos could significantly improve autism-like behaviors associated with ASD.
The team previously showed that transplanting human bone marrow mesenchymal stem cells (MSCs) into the lateral ventricles of BTBR mice resulted in long-term improvements in their autistic behavior phenotypes. Recent studies point to exosomes as major mediators of the therapeutic effect of MSCs. In this study, Tel Aviv scientists tested whether treatment with MSC-secreted exosomes (MSC-exo) would demonstrate similar beneficial effects. Notably, BTBR mice treated with MSC-Exo showed improved male-male social interaction and decreased repetitive behavior during social interaction.
More complex and prolonged ultrasonic vocalizations from males to females were seen in BTBR animals treated with MSC-Exo, making them more similar to healthy control mice. Additionally, MSC-Exos significantly improved the pup-finding behavior of female BTBR mice. BTBR females given normal saline returned only two of 24 pups to the nest, while BTBR females given MSC-Exos returned all (18/18) of the pups, showing significant improvement in maternal behavior. No negative symptoms were detected after intranasal administration of MSC-exo in BTBR or healthy mice. The significant beneficial effects of exosomes in BTBR mice may lead to the development of a new, non-invasive therapeutic strategy to reduce ASD symptoms.
There is no longer any doubt that intravenous administration of umbilical cord blood can bring tangible benefits to children and adults with disorders of the nervous system (ASD, cerebral palsy, cerebral palsy, organic brain damage, etc.). This is evidenced by the results of international and our own clinical studies.
However, parents often do not understand the difference between umbilical cord blood stem cell transplantation and intravenous cord blood administration for the treatment of neurological diseases?
First of all, let’s explain a number of terms aboutstem cells:
Stem cells from umbilical cord tissue are called mesenchymal stromal cells or MSCs.
Stem cells from umbilical cord blood are called hematopoietic stem cells or HSCs.
They give rise to all blood cells and immune cells. This allows the use of HSCs to restore normal blood function lost as a result of disease: leukemia (blood cancer), pernicious anemia, etc.
At the same time, for treatment, HSCs must “populate” the patient’s body. Therefore, before transplantation, the patient’s own hematopoietic cells are “killed” with high doses of chemotherapy, and then hematopoiesis is restored using healthy HSCs from donor cord blood, which engraft and create a new permanent immune system.
Treatment with cord blood for disorders of the development of the nervous system is a completely different technique that provides new additional resources to the body for its restoration!
The patient does not need a course of aggressive preparation. Cord blood cells are used as a unique “living elixir”.
They will launch a whole cascade of restorative reactions in the patient, including activating the formation of new healthy nerve cells, “teaching” diseased cells how to reprogram themselves to restore and interact correctly with each other, returning normal function to tissues and organs.
Researchers from Stanford University School of Medicine have tested a new potential treatment for Alzheimer’s disease in mice. Transplantation of blood stem cells from healthy animals to patients helps to replace defective nerve cells.
The researchers experimented with mice that had defective TREM2 genes, the most common genetic change associated with a high risk of developing Alzheimer’s disease. The researchers transplanted stem cells and progenitor cells isolated from the blood of healthy animals into these animals.
The analysis showed that the transplanted cells restore the circulatory system in the recipient’s brain and even form new cells that look and function like microglia — macrophages of the nervous system, dysfunctions in which are associated with the development of Alzheimer’s disease.
The new cells replaced many of the recipient’s original microglia and, as shown by preliminary analysis, restored their function. In addition, the transplant also affected other signs of Alzheimer’s disease, including a decrease in the formation of amyloid plaques. «We showed that most of the original brain microglia was replaced by healthy cells, which led to the restoration of normal TREM2 activity,» says Marius Wernig, co—author of the study.
The researchers note that although the first results are promising, they are preliminary and require further research. Firstly, the replacement cells resemble microglia, but still differ from it. It is necessary to study how these changes will affect brain function in a long-term study.
And secondly, the current treatment is invasive — replacement requires first destroying the diseased cells with radiation or chemotherapy. For the full application of the method in humans, a less toxic method of removing cells with impaired functions is needed.
Scientists have developed a genome editing system that has successfully modified the DNA of mice with a mutation similar to that found in people with autism spectrum disorder (ASD), writes SCMP.
The article says special mice were bred for research with a mutation in the MEF2C gene, which they say is “strongly associated” with the disorder. Thus, mutations in this gene cause developmental disorders, speech problems, repetitive behavior and epilepsy, rbc.ru reports.
The developed system for editing the MEF2C gene was called AeCBE. As the study authors note, mice that received a special injection showed a decrease in behavior associated with ASD. The scientists emphasized that the potential treatment could be used not only for patients with ASD, but also for other genetic neurodevelopmental disorders.
A professor at East China Normal University told SCMP that this is the first effective treatment for mice with mutations associated with ASD. The injection would go directly into the mouse’s brain, he said, so scientists needed to learn how to safely interact with the blood-brain barrier, a group of cells that regulate the entry of foreign molecules into the brain. By studying mouse brain cells, the researchers found that AeCBE was able to “make repairs” throughout the brain with about 20% accuracy, which was enough to boost MEF2C protein levels, SCMP writes. “The treatment successfully restored MEF2C protein levels in several brain regions and reversed behavioral abnormalities in mice with the MEF2C mutation,” the paper states.
The exact cause of ASD is still unknown, but it is believed that 80–90% of cases are due to genetic predisposition. More than 100 genes have already been found that scientists associate with the occurrence of autism. But there are also environmental factors that can also contribute to the development of this disorder in a child. For example, inflammation in the mother’s body during pregnancy has been linked to an increased risk of ASD in the child. It can occur due to chronic diseases: arthritis, lupus or diabetes, and can also be triggered by obesity due to cytokines that penetrate the blood-brain barrier and attack neural networks.
Some people diagnosed with ASD as children outgrow it, achieving an “optimal outcome.” The term was coined by Deborah Fine, a professor of psychology at the University of Connecticut in Storrs. In 2013, she conducted research with 34 people diagnosed with autism. In 2016, scientists reviewed cases of “optimal outcomes” and concluded that it is possible to talk about loss of diagnosis only if it is made early. Timely, intensive behavioral intervention plays an equally important role. A large proportion of people with autism maintain symptoms consistent with the diagnosis and require therapy and support throughout their lives.
MSCs are multipotent stromal cells, which means they can differentiate into different cell types. Originating mainly from bone marrow, they can also be found in various other tissues such as fat, umbilical cord blood, dental pulp, etc. Unlike other stem cells, mesenchymal stem cells (MSCs) have a special detection principle immune system, which reduces the likelihood of rejection when transplanted into the recipient, making them stronger candidates for therapeutic use.
Therapeutic potential of degenerative diseases
Osteoarthritis: Osteoarthritis (OA), one of the most common degenerative joint diseases, destroys cartilage and leads to joint pain and stiffness. MSCs show promising efficacy in OA by promoting cartilage repair. When injected into an affected joint, these cells can promote cartilage regeneration, support pain reduction, and improve joint functionality.
Spinal Cord Injuries: Traumatic injuries to the spinal cord can lead to paralysis and a variety of other conditions. In recent studies, MSCs have demonstrated the ability to deplete and stimulate neuronal growth, creating a favorable environment for spinal cord repair.
Cardiovascular disease: After a heart attack, heart tissue may be permanently damaged. MSCs were studied for their ability to regenerate cardiac tissue. Their ability to differentiate into cardiomyocytes, combined with anti-inflammatory and angiogenic substances, makes them effective in the fight against heart disease.
Neurodegenerative disease: Conditions such as Parkinson's and Alzheimer's diseases are characterized by the progressive degeneration of nerve cells. MSCs can provide a supportive environment, provide neuroprotection, and even replace lost cells, although research in this area is still in its early stages.
Longevity treatment
In addition to degenerative diseases, MSCs are of great importance in the field of longevity and anti-aging treatments. Aging is essentially a degenerative process characterized by cell destruction. Here’s how to awaken MSC:
Anti-inflammatory properties: Chronic nutrition plays a key role in aging. MSC uses effective anti-inflammatory mechanisms that can mitigate this process, ensuring a slowdown in the aging process at the cellular level.
Tissue repair and regeneration: As we age, our body's ability to repair and regenerate declines. The introduction of MSCs can enhance these processes, rejuvenating tissues and possibly extending lifespan.
Mitochondrial Support: Mitochondria, the powerhouses of our cells, deteriorate as we age. MSC can support mitochondrial health, causing cells to produce the energy needed to maintain resilience.
Finally
Mesenchymal stem cells, with their uniqueness and versatility, are currently leaders in regenerative medicine. Their potential for the future of degenerative diseases and longevity is enormous. However, it is important to approach their therapeutic use with cautious optimism. Although early results are promising, continued research is critical to fully exploit its potential and ensure patient safety. As science advances, MSC may well rewrite the history of aging and degeneration.
