Water Disinfectant linked to Congenital Heart Disease in Infants
Megha Gupta
Research Assistant, exRNA Therapeutics
Water is essential for life, but what if something meant to keep it clean could potentially harm the most vulnerable among us?
In recent years, research has shed light on the potential link between disinfectants in water and the development of congenital heart diseases (CHDs) in babies born to pregnant women. Disinfectants are crucial for maintaining water quality by eliminating harmful microorganisms that can cause waterborne diseases. Chlorine, chloramines, and ozone are commonly used disinfectants in water treatment facilities worldwide. While these chemicals effectively kill pathogens, they can also react with organic matter in water to form disinfection by-products (DBPs), such as trihalomethanes (THMs) and haloacetic acids (HAAs). Congenital heart disease refers to heart problems present at birth, ranging from minor to severe. Symptoms may include difficulty breathing, poor feeding, and bluish skin. Complications can lead to heart failure, irregular heartbeats, and developmental delays. Treatment options vary based on the severity of the condition and may include medication or surgery.
The Link to Congenital Heart Diseases:
Studies have suggested a potential association between maternal exposure to DBPs in drinking water and an increased risk of CHDs in newborns. Researchers have found that certain DBPs can cross the placental barrier and interfere with fetal development during critical stages, particularly affecting the formation of the heart and cardiovascular system. Prolonged exposure to elevated levels of DBPs, especially during early pregnancy, may disrupt normal cardiac development and contribute to the onset of CHDs in infants. Several epidemiological studies have investigated the relationship between maternal DBP exposure and the incidence of CHDs in offspring. These studies have reported associations between elevated levels of DBPs in drinking water and an increased risk of CHDs, including atrial septal defects and ventricular septal defects, in newborns. As precaution, pregnant women can consider consuming bottled or filtered water from reputable sources to reduce reliance on chlorinated tap water, especially during pregnancy. The association between water disinfectants and CHDs in infants underscores the importance of understanding and mitigating environmental risk factors during pregnancy.
Treatment of DMD with Smart shots; a Cocktail ASO therapy!!
Akanksha Kumari
Research Assistant, exRNA Therapeutics
DG9-PMO and G1, both ASO cocktails are two different approaches to treat Duchenne muscular dystrophy (DMD), a condition that affects muscles and makes it difficult for people to move. DG9-PMO aims to make the treatment better by using a lesser quantity of PMOs(phosphorodiamidate morpholino oligomers). These PMOs are important because they help fix the genetic problem that causes DMD. By using less PMOs, the treatment could work better, making patients feel stronger and healthier. Reducing the amount of PMOs could make the treatment safer by lowering the chances of unwanted or off-target effects. This can be important because this can make sure the treatment helps without causing side effects. Plus, using fewer PMOs might make the treatment cheaper, which means more people could afford it. This is good news because it could help more people with DMD get the treatment they need. On the other hand, G1 ASO cocktail is another way to treat DMD. This cocktail also targets the genetic problem causing DMD but in a different way. It has a special G-rich sequence, which helps it work better. Instead of being injected, like DG9-PMO, it's given through the nose, which can be easier for patients. G1 ASO cocktail has shown, it can improve the heart and muscles of people with DMD. It helps the heart work better and makes the muscles stronger. Both treatments have their advantages. DG9-PMO could be good because it uses less medicine, making it potentially safer and cheaper. But G1 ASO cocktail is promising too because it can improve both heart and muscle health, and it's easier to take. In the end, both treatments are working towards the same goal: helping people with DMD live healthier lives.
The Maternal mRNA Mystery: Its Knockdown and the Impact on Baby's Brain!
Sapna Kumari
Research Assistant, exRNA Therapeutics
CNOT1, a core component of the CCR4-NOT complex, is pivotal in mRNA deadenylation, crucial for mRNA turnover and regulation. Depletion of CNOT1 can disrupt the delicate balance of maternal (mother) and zygotic (baby’s) mRNA stability, potentially leading to severe developmental and neurological abnormalities. Researchers can precisely control CNOT1 expression using a doxycycline-inducible system impacting mRNA stability. Maternal mRNA, essential for early embryonic development, may accumulate due to impaired degradation, resulting in abnormal protein levels crucial for early developmental processes. Conversely, zygotic mRNA instability can occur, hindering essential protein production for embryonic development, possibly leading to severe defects or embryonic lethality. Knockdown or mutation of CNOT1 could lead to defects in neural cell differentiation, affecting brain structure and function leading to cognitive deficits and neurodevelopmental disorders. Although maternal mRNA stability may initially be affected, the more critical effects manifest in zygotic mRNA instability, particularly in the nervous system. exRNA Therapeutic’s drug G1 can have potential to address CNOT1 gene mutations by restoring normal CNOT1 function, stabilizing maternal and zygotic mRNAs, supporting proper protein synthesis, and potentially preventing developmental and neurological disorders. This could lead to healthier embryonic development and long-term neurological health, highlighting the therapeutic potential of G1 for conditions arising from CNOT1 mutations.
The Impact of Antibiotic Doxycycline on Male Fertility and the Possible G1 Solution
Sapna Kumari
Research Assistant, exRNA Therapeutics
One common antibiotic that is well-known for working against a variety of bacterial infections is doxycycline. Recent studies, however, indicate that using it might have unforeseen consequences for male fertility. When doxycycline is introduced into the body, it decreases the levels of miR-486-5p. This reduction disrupts the normal regulatory functions of miR-486-5p, setting off a cascade of molecular events. One of the critical genes affected by the decrease in miR-486-5p is CNOT1. CNOT1 is vital for maintaining the integrity and functionality of sperm cells. When CNOT1 levels drop, sperm cells begin to degrade, losing their viability and health.The morphology, or structure, of sperm cells is crucial for their ability to move and fertilize an egg. Downregulated CNOT1 leads to abnormalities in sperm morphology, resulting in defective shapes that hinder their motility and function. CNOT1 is part of the CCR4-NOT complex, which is essential for various cellular processes, including mRNA degradation and gene expression regulation. With reduced miR-486-5p levels, the expression of CNOT1 is downregulated, meaning the gene produces less of its corresponding protein.
So, we introduced G1 which is designed to restore the balance disrupted by doxycycline. It works by increasing the levels of miR-486-5p, thereby reversing the downregulation of CNOT1.
By boosting miR-486-5p levels, G1 helps normalize CNOT1 expression, which is crucial for maintaining healthy sperm cells.With CNOT1 levels restored, sperm cells regain their structural integrity and functionality. This leads to improved sperm morphology and motility, enhancing their ability to fertilize an egg.The overall quality of sperm improves, addressing the root causes of doxycycline-induced male infertility. Hence, Doxycycline, despite its effectiveness as an antibiotic, poses risks to male fertility through its impact on miR-486-5p and subsequent downregulation of CNOT1. This molecular cascade leads to sperm degradation and morphological changes, resulting in infertility. However, the development of the G1 drug offers a beacon of hope. By restoring miR-486-5p levels and normalizing CNOT1 expression, G1 has the potential to mitigate these adverse effects and improve sperm health, providing a viable solution for those affected by doxycycline-induced fertility issues.In order to support your journey towards parenting and to restore fertility, we can offer advice on possible therapies, such as the exciting G1 medication.
Understanding the Role of Utrophin in Muscular Dystrophy Treatments- Upregulation therapy
Shivam Yadav
Research Assistant, exRNA Therapeutics
Dystrophin vs. Utrophin
Dystrophin is predominantly located at the sarcolemma of muscle fibers, where it plays a vital role in connecting the cytoskeleton of the muscle cell to the extracellular matrix. Utrophin, a structural homologue of dystrophin, shares considerable sequence similarity and functional properties with dystrophin. Unlike dystrophin, utrophin is normally found at the neuromuscular junctions (NMJ) and is upregulated in response to muscle damage and during the early stages of muscle development .
Potential of Utrophin as a Therapeutic Agent
Given the structural and functional similarities between utrophin and dystrophin, it is hypothesized that upregulating utrophin could compensate for the lack of dystrophin in DMD patients, thereby partially protecting muscle fibers from degeneration. This compensatory mechanism can stabilize the muscle cell membrane and diminish the symptoms of dystrophin deficiency.
Alternatively, utrophin up-regulation could be the consequence of muscle regeneration since this phenomenon is also observed in dystrophin-positive myopathies.
Mechanisms to Increase Utrophin Expression
Several strategies have been explored to upregulate utrophin expression in dystrophin-deficient muscles, including:
1. Aryl Hydrocarbon Receptor (AhR) Antagonists:
- AhR antagonists such as ezutromid have been found to increase utrophin levels by binding to and inhibiting the AhR pathway . The interaction of AhR antagonists with the receptor can lead to enhanced utrophin expression, independent of the mutation type in the DMD gene.
2. Peroxisome Proliferator-Activated Receptor (PPAR) Agonists:
- These compounds activate PPAR, which plays a role in the regulation of lipid metabolism and inflammation, and may contribute to increased utrophin expression indirectly .
4. AMP-Activated Protein Kinase (AMPK) Activators:
- AMPK activators boost cellular energy levels and are implicated in modulating metabolic pathways that can enhance utrophin synthesis.
5. TIPARP/PARP7 Pathway:
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-adenosine diphosphate (ADP)-ribose polymerase (TIPARP/PARP7).
TIPARP/PARP7, an AhR target gene and mono-ADP-ribosyltransferase, represses AhR signaling through a negative feedback loop. Upregulating TIPARP could indirectly boost - utrophin levels by attenuating AhR-mediated downregulation of utrophin.
PARP7 acts to negatively regulate the expression of the AHR-target cytochrome P450 genes, CYP1A1 and CYP1B1.
Conclusion
Upregulating utrophin presents a promising therapeutic strategy for DMD, aiming to alleviate muscle degeneration symptoms by compensating for the missing dystrophin. Innovations in the discovery and development of AhR antagonists, PPAR agonists, and other modulators are paving the way for potential treatments that could impact the lives of DMD patients significantly.
Diagnosis of Autism Spectrum Disorder (ASD) using microRNAs (miRNA)
Ankita Sharma
Research Assistant, exRNA Therapeutics
Introduction of Autism Spectrum Disorder (ASD)
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex clinical manifestations that arise between 18 and 36 months of age. Social interaction deficiencies, a restricted range of interests, and repetitive stereotyped behaviors are the main characteristics of ASD, which are sometimes difficult to detect early. The conventional methods of detecting Autism Spectrum Disorder (ASD) include a combination of behavioral assessments and psychological evaluations. So, sometimes it can be misdiagnosed.
Introduction of microRNA (miRNA)
MiRNAs, the most well-studied non-coding ribonucleic acid (ncRN), are short non-coding RNAs of approximately 18–22 nucleotides that are responsible for regulating gene expression through epigenetic mechanisms in approximately 60% of human genes. miRNAs are heavily involved in neuronal plasticity and neuronal development, and their deregulation generates diverse neurological alterations, such as ASD.
microRNA as a biomarkers
miRNAs as biomarkers for ASD can be used as biomarkers to support diagnosis that focused on biogenesis and measurement in different biofluids or tissues for detection, such as lymphoblastoid cells, postmortem cerebral cortex tissues, serum or blood plasma, olfactory mucosa cells, and saliva.
Several studies such as miR-151a, miR-146a, and miR-27a-30 are dysregulated in people with ASD and are replicated in more than one tissue.
Although 218 miRNAs were identified which are associated with ASD. Most frequently dysregulated miRNAs in patients with ASD were miR-451a, miR-144-3p, miR-23b, miR-106b, 150-5p, 320a, 92a-2-5p, and 486-3p miR-451 is associated with impaired social interaction, miR-106 family is associated with repetitive behaviors, miR-486-3p is associated with intelligence, miR-140-3p is associated with memory and learning, and no studies miRNA was associated with language impairment.
Conclusion
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by social interaction deficits, restricted interests, and repetitive behaviors. Diagnosis can be challenging, often relying on behavioral assessments and psychological evaluations, leading to potential misdiagnosis. Research suggests that miRNAs, short non-coding RNAs regulating gene expression, play a crucial role in neuronal development and plasticity, with their dysregulation linked to ASD. Several miRNAs, including miR-151a, miR-146a, and miR-27a-30, are found to be dysregulated in ASD across various tissues. Among the identified miRNAs associated with ASD, miR-451a, miR-144-3p, miR-23b, miR-106b, miR-150-5p, miR-320a, miR-92a-2-5p, and miR-486-3p are frequently implicated. Notably, miR-451 is linked to impaired social interaction, the miR-106 family to repetitive behaviors, miR-486-3p to intelligence, and miR-140-3p to memory and learning, while no specific miRNA has been associated with language impairment in ASD.
Incorporating the collection and analysis of saliva and serum or blood plasma as part of ASD evaluation showcases a promising avenue for early detection and intervention. This approach not only streamlines the diagnostic process but also underscores the importance of timely identification for better management of ASD.
Revolutionizing Cancer Treatment with G1: An Antisense Oligonucleotide Breakthrough Targeting RCCD1
Md. Mahfooz Khan
Research Assistant, exRNA Therapeutics
Understanding RCCD1 and Its Role in Disease
RCCD1 (Regulator of Chromosome Condensation Domain-Containing 1) is a protein that plays a crucial role in several cellular processes, including DNA repair, chromatin remodeling, and cell cycle regulation. These functions are essential for maintaining genomic stability and ensuring that cells grow and divide correctly. Proper functioning of RCCD1 ensures that the DNA is accurately replicated and any damage is repaired before the cell proceeds to divide.
When RCCD1 is underactive or its function is compromised, cells can experience issues with DNA repair and cell cycle regulation. This can lead to genomic instability and the accumulation of genetic mutations, which can drive the development and progression of cancer. RCCD1 downregulation has been specifically associated with various types of cancer, including lung and ovarian cancers, where it contributes to the uncontrolled cell growth that characterizes these diseases.
The Challenge of Downregulated RCCD1
In cases where RCCD1 is downregulated, cells lose their ability to properly regulate the cell cycle and repair DNA damage. This dysregulation can result in cells entering the cell cycle inappropriately or failing to arrest when damage is detected, leading to unchecked cell division and tumor formation. The loss of RCCD1 function creates a cellular environment that is conducive to cancer development, making it an important target for cancer therapy.
Restoring the normal function of RCCD1 in cancer cells could help to reinstate proper cell cycle control and DNA repair mechanisms. This, in turn, could inhibit tumor growth and progression. As such, developing therapeutic strategies that can modulate RCCD1 activity represents a promising approach for cancer treatment.
How G1, an Antisense Oligonucleotide, Works
G1 is a novel antisense oligonucleotide (ASO) designed to address the problem of RCCD1 downregulation. Antisense oligonucleotides are short, synthetic strands of nucleic acids that can bind to specific RNA molecules, preventing them from carrying out their function.
G1 works by downregulating RCCD-AS1, the antisense RNA that negatively regulates RCCD1. By reducing RCCD-AS1 levels, G1 indirectly boosts the activity of RCCD1. This increase in RCCD1 activity helps restore normal cell function, inhibiting the uncontrolled cell growth seen in cancer.
The Therapeutic Potential of G1
By targeting the regulatory RNA RCCD-AS1, G1 has the potential to be an effective treatment for cancers where RCCD1 is crucial. This innovative mechanism highlights the therapeutic promise of G1, as it not only aims to prevent tumor growth but also to restore and maintain healthy cellular functions. Enhancing RCCD1 activity through G1 offers a novel approach to cancer therapy, potentially providing significant benefits to patients with cancers linked to RCCD1 dysregulation.
Conclusion
The development of G1 exemplifies the potential of targeted antisense oligonucleotide therapies in combating challenging diseases. By enhancing RCCD1 activity, G1 holds promise as a potent therapeutic agent against cancers and other conditions involving RCCD1 dysregulation. Ongoing research aims to explore the full potential of G1, striving to make a significant impact on patient health and treatment outcomes. Through innovative mechanisms like those of G1, targeted therapies continue to advance, offering new hope for effective cancer treatments.
The Potential of ACVR2B Inhibition by Antisense Oligonucleotides for Duchenne Muscular Dystrophy
Shivam Yadav
Research assistant, exRNA Therapeutics
Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy characterized by rapid progression of muscle degeneration, leading to muscle weakness and loss of skeletal muscle mass. It is caused by mutations in the DMD gene, which encodes dystrophin, a protein crucial for maintaining muscle cell integrity. The birth prevalence is estimated to be 1 in every 3,500 live male births. Age of onset is usually between 3 and 5 years of age.
Role of Myostatin in Muscle Growth
Myostatin, also known as Growth Differentiation Factor 8 (GDF-8), is a member of the TGF-beta superfamily and acts as a potent negative regulator of muscle growth. It is predominantly expressed in skeletal muscle tissue, where it limits muscle growth and differentiation. Studies have shown that homozygous disruption of the myostatin gene results in a significant increase in muscle mass, with individual muscles becoming 2–3 times larger than normal.
Myostatin Inhibition as a Therapeutic Strategy
Given its role in negatively regulating muscle growth, inhibiting the myostatin pathway has emerged as a promising therapeutic approach to enhance muscle mass and function. This strategy is particularly relevant for conditions like DMD, where muscle preservation and enhancement are critical.
Activin Type 2 Receptors: ACVR2A and ACVR2B
ACVR2A and ACVR2B are activin type 2 receptors that modulate signals for transforming growth factor beta (TGF-beta) ligands. These receptors are pivotal in various physiological processes including growth, cell differentiation, homeostasis, osteogenesis, and apoptosis. Specifically, ACVR2A and ACVR2B play essential roles in muscle growth regulation by acting as binding sites for myostatin. ACVR2B serves as a negative regulator of skeletal muscle growth, essentially mediating the inhibitory effects of myostatin.
The Mdx Mouse Model in Myostatin Research
The mdx mouse model, which serves as a widely used experimental system for studying DMD, exhibits significantly higher levels of myostatin compared to humans with DMD. This model has been instrumental in evaluating the effects of myostatin inhibition on muscle mass and function.
ACVR2B Inhibition: A Promising Approach
Blocking ACVR2B or its ligands and downstream signaling pathways has shown favorable outcomes in preserving muscle mass in preclinical studies. In rodent models bearing experimental cancers or undergoing chemotherapy, inhibiting ACVR2B preserved muscle mass, highlighting the therapeutic potential of this approach.
Antisense Oligonucleotides (ASOs) in ACVR2B Inhibition
Antisense oligonucleotides (ASOs) are designed to specifically bind to target RNA sequences, modulating gene expression. By designing ASOs to inhibit ACVR2B expression, it is possible to reduce the effects of myostatin, thereby promoting muscle growth and function. This therapeutic strategy could be particularly beneficial for DMD patients by enhancing muscle mass and strength, potentially slowing disease progression.
Conclusion
Combining ACVR2B inhibition with other therapeutic approaches, such as gene therapy, could provide a more comprehensive treatment strategy for DMD. The use of antisense oligonucleotides to inhibit ACVR2B offers a promising avenue for enhancing muscle growth and function, thereby improving the quality of life for individuals with DMD.
Beyond the Womb: Nasal Drops Pioneer Genetic Healing for Unborn Babies
Khusi Kumari
Research Assistant, exRNA therapeutics
Nasal Drops Deliver Gene-Modifying Drugs to Fetal Tissues
ASOs administered via nasal drops are absorbed through the nasal mucosa into the maternal bloodstream. From there, they travel through the maternal systemic circulation. To cross the placental barrier, ASOs utilize mechanisms such as binding to placental receptors like ASGRs, active transport by transporter proteins like P-GP and ENT1, and processes like endocytosis and exocytosis involving specific receptors. Once across the placenta, ASOs enter the fetal circulation through the umbilical vein. This ensures their distribution to various fetal tissues, with significant accumulation in organs like the liver and kidney. In fetal tissues, ASOs modulate gene expression by binding to target mRNA sequences, thereby correcting defective gene expression caused by genetic mutations. This process involves mechanisms such as steric hindrance, induction of RNase H activity, and alteration of splicing. Additionally, ASOs administered intranasally may affect olfactory receptors in the fetal nasal epithelium, facilitating transport to the brain. The involvement of receptors like FcRn and NMDARs also potentially aids in the transfer and transport of ASOs to fetal tissues.
Fetal Genetic Correction: ASO's Journey for Therapy
ASOs, therapeutic agents administered to pregnant women via nasal drops, embark on a journey through the maternal bloodstream to reach the developing fetus. They overcome the placental barrier through receptor binding, active transport, and other mechanisms. Traveling through the umbilical cord, they target fetal tissues, especially the liver and kidney, to modulate gene expression by binding to specific mRNA sequences. Along the way, they utilize olfactory receptors, the FcRn receptor, NMDAR activation, and passive diffusion for uptake. This journey highlights the complex yet effective delivery of ASOs to the fetus for genetic correction.
New Therapy Targets Angelman Syndrome with Nasal Drops
Antisense oligonucleotides (ASOs) are synthetic molecules designed to target specific mRNA sequences. In the context of Angelman Syndrome, ASOs are administered to pregnant women via nasal drops, allowing them to cross the placental barrier and reach the fetus. Once inside the fetal tissues, ASOs bind to the mutated mRNA derived from the UBE3A gene, correcting the gene expression imbalance responsible for Angelman Syndrome. This correction restores the production of functional UBE3A protein, potentially alleviating the symptoms of the disorder. Overall, ASOs offer a promising therapeutic approach for treating Angelman Syndrome by targeting the underlying genetic abnormalities.
Navigating the Risks of Antidepressant Use During Pregnancy
Megha Gupta
Research Assistant, exRNA Therapeutics
In the complex landscape of pregnancy, ensuring the health and well-being of both mother and child is paramount. However, a lesser-known concern has been emerging in recent years: the potential link between antidepressant use during pregnancy and the development of congenital heart diseases (CHDs) in infants. While antidepressants have been a boon for managing maternal mental health, their effects on fetal development, particularly on the heart, warrant a closer examination. Antidepressants are commonly prescribed to pregnant women to alleviate symptoms of depression, anxiety, and other mood disorders. However, several studies have indicated a correlation between certain antidepressants and an increased risk of CHDs in newborns. One such class of antidepressants is selective serotonin reuptake inhibitors (SSRIs), which includes fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). Research suggests that exposure to SSRIs during pregnancy may disrupt the normal development of the fetal heart, leading to structural abnormalities. For example, a study published in the New England Journal of Medicine found that women who took paroxetine during the first trimester of pregnancy had a significantly higher risk of giving birth to infants with septal heart defects, where there is a hole in the wall that separates the heart's chambers. Similarly, another study published in JAMA Pediatrics reported an association between maternal use of sertraline during early pregnancy and an elevated risk of ventricular /septal defects (VSDs), a type of CHD characterized by abnormal openings between the heart's lower chambers. The mechanisms through which antidepressants contribute to CHDs in infants are not yet fully understood. However, it is believed that these medications may interfere with serotonin signaling, which plays a crucial role in heart development during embryogenesis. Disruption of this signaling pathway could lead to malformations in the developing heart. It's essential for healthcare providers and expectant mothers to weigh the risks and benefits of antidepressant use during pregnancy. For some women, the benefits of managing their mental health condition may outweigh the potential risks of medication. In such cases, close monitoring and collaboration between the patient and healthcare provider are crucial to ensure the best possible outcomes for both mother and child.
Alternative treatment options, such as therapy, lifestyle modifications, and non-pharmacological interventions, should also be considered for managing maternal mental health during pregnancy. Additionally, for women who require antidepressant medication, choosing the safest option with the least potential for adverse effects on fetal development is paramount. This may involve switching to a different class of antidepressants or adjusting the dosage under medical supervision.
In conclusion, while antidepressants have proven efficacy in treating maternal mental health disorders, their use during pregnancy requires careful consideration due to the potential risk of congenital heart diseases in infants. Healthcare providers should engage in comprehensive discussions with pregnant patients regarding the risks and benefits of antidepressant therapy, ensuring informed decision-making and personalized care. Ultimately, prioritizing the health and well-being of both mother and child is essential in navigating the complexities of pregnancy and mental health management.
Albumin Helps Tocopherol And ASO Reach Our Cells
Khusi Kumari
Research Assistant, exRNA Therapeutics
Dynamic Duo: Vitamin E and Albumin Fortify Cellular Health Against Oxidative Stress
Vitamin E, a potent antioxidant, and albumin, the most abundant protein in the blood plasma, form a dynamic duo in safeguarding cellular health against oxidative stress. This partnership underscores the intricate interplay between nutrients and proteins within the human body.
Albumin: Vitamin E's Silent Partner in Cellular Defense
Upon ingestion, vitamin E undergoes absorption in the intestine and enters the bloodstream, where it associates primarily with lipoproteins for transportation to various tissues and organs. However, a fraction of vitamin E also binds to albumin, forming a complex that extends its reach and enhances its stability in circulation.Albumin serves as a carrier protein, shuttling various substances, including vitamins, hormones, and drugs, throughout the body. Its high affinity for vitamin E allows for efficient transport and delivery to cells in need of antioxidant protection.
Guardians at the Gate: How Vitamin E-Albumin Complexes Defend Cell Membranes
As vitamin E-Albumin complexes reach their destinations within cell membranes, they play a pivotal role in intercepting free radicals, reactive molecules that can induce oxidative damage and impair cellular function. By neutralizing these free radicals, the vitamin E-Albumin complex helps maintain the integrity of cell membranes and preserves cellular health.
Furthermore, albumin's ability to bind to multiple molecules, including fatty acids and bilirubin, complements the antioxidant function of vitamin E by preventing the accumulation of lipid peroxides and other harmful byproducts of oxidative stress.
Protein Dynamics in Blood: IgG, Albumin, and FcRn Interactions Unveiled
IgG and albumin can simultaneously bind to FcRn, although the orientation of FcRn may favor IgG binding over albumin due to steric clashes caused by IgG's Fab arms. Surprisingly, there's a positive correlation between IgG and albumin levels, despite expectations of a negative correlation. Albumin, a simple protein found in various physiological fluids and tissues, plays critical roles like maintaining osmotic pressure, transporting substances in the blood, and neutralizing free radicals. Increased IgG levels can decrease serum albumin levels due to competition for limited space in the blood, as both are types of blood proteins. Similarly, disorders impairing fat absorption, essential for vitamin E absorption, can lead to vitamin E deficiency and decreased serum albumin levels due to competition among proteins for blood space."
Critical Connections: Albumin Dysfunction and Vitamin E Delivery's Impact on Oxidative Damage
However, disruptions in albumin levels or function, as seen in certain medical conditions such as liver or kidney disease, can compromise the delivery of vitamin E to target tissues, leading to increased susceptibility to oxidative damage and related pathologies.
In summary, the collaboration between vitamin E and albumin exemplifies the intricate synergy between nutrients and proteins in maintaining cellular homeostasis. This partnership highlights the importance of adequate vitamin E intake and optimal albumin function in promoting overall health and resilience against oxidative stress-induced diseases.
Tiny RNA, Big Impact: Revolutionizing Crohn's Disease Treatment with miRNA Therapy!!
Lubnaa Firoz
Research Assistant, exRNA Therapeutics
Crohn’s disease (CD) and ulcerative colitis (UC) are a form of Inflammatory Bowel Disease (IBD), representing a group of chronic inflammatory conditions of the gastrointestinal tract with complex pathogenesis. Affecting millions worldwide, Crohn's disease significantly impacts patients' quality of life, causing symptoms like severe abdominal pain, diarrhea, weight loss, and fatigue.it involves a complex interplay of genetic, environmental, and immune factors. Mutations in genes like NOD2, ATG16L1, and IL23R are commonly associated with the disease and contribute to its hereditary nature.
Despite significant advancements, current treatments often fall short of providing a lasting solution. Enter microRNAs (miRNAs) – small, non-coding RNA molecules that have emerged as key regulators of gene expression and potential game-changers in crohn's disease. This blog explores the crucial role of miRNAs in crohn's and the innovative therapeutic strategies being developed.
miRNA Therapy: A Promising Approach
MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally by binding to target messenger RNAs (mRNAs). This binding can either inhibit mRNA translation or promote its degradation.
How miRNA Therapy Alleviate Crohn's Disease Symptoms
miRNA therapy offers a novel approach to managing Crohn's disease by directly targeting the NF-κB and MAPK signaling pathways involved in inflammation and immune dysregulation. In Crohn's disease, miRNAs regulate key genes like NOD2, IL-10, and TNF-α, which are crucial in controlling these pathways. miRNA therapy seeks to correct imbalances in miRNA activity, thereby restoring proper regulation of these genes and reducing inflammation.
Restoring Down Regulated miRNAs:
miRNA Mimics:In Crohn's disease, miRNAs like miR-192 and miR-375 are downregulated, impairing intestinal barrier function and increasing inflammation. Upregulating these miRNAs with synthetic mimics can restore their protective roles. miR-192 enhances tight junction proteins (occludin, ZO-1) and downregulates pro-inflammatory genes (IL-6, MMPs), while miR-375 inhibits inflammatory genes (TNF-α, NF-κB pathways) and regulates epithelial cell turnover and apoptosis. This approach can strengthen the intestinal barrier, reduce inflammation, and promote mucosal healing, offering a promising treatment for Crohn's disease by targeting key molecular pathways.
Inhibiting Upregulated miRNAs:
Antagomirs (Anti-miRNAs):. In Crohn's disease, miR-21 and miR-155 are upregulated, contributing to inflammation. Antagomirs inhibit these miRNAs to reduce symptoms. miR-21 Increases cytokine production via NF-κB pathway. Antagomirs reduce NF-κB activation, decreasing inflammation. miR-155 Promotes inflammation by targeting SOCS1 pathway. Antagomirs restore SOCS1 levels, balancing immune response.
Therapeutic Potential: miR-21 Antagomirs Decrease cytokine production and inflammation. miR-155 Antagomirs Balance immune response and alleviate symptoms. Targeting these pathways with antagomirs offers a promising approach to managing Crohn's disease.
Sequestering Overactive miRNAs:
miRNA Sponges: These are RNA molecules engineered to contain multiple binding sites for specific miRNAs. They effectively sequester overactive miRNAs away from their natural targets. For example, miRNA sponges targeting miR-155 can prevent it from exacerbating inflammation, thereby reducing intestinal damage and promoting healing.
In conclusion, miRNA therapy represents a groundbreaking approach to treating Crohn's disease by targeting the molecular mechanisms underlying inflammation and immune dysregulation. Through miRNA mimics, antagomirs, and miRNA sponges, it is possible to restore miRNA balance, reduce inflammation, and improve patient outcomes.
The ABAT Gene: Essential for Neural Balance and Preventing Seizures
Shivam Yadav
Research Assistant, exRNA Therapeutics
The ABAT gene is a critical component in our neurological system, primarily responsible for producing the enzyme GABA-transaminase. This enzyme is central to the regulation of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter.
Why GABA is Important
Gamma-aminobutyric acid (GABA) is an amino acid that serves as the primary inhibitory neurotransmitter in the brain and a major inhibitory neurotransmitter in the spinal cord. GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase, an enzyme which uses vitamin B6 (pyridoxine) as a cofactor. After synthesis, it is loaded into synaptic vesicles by the vesicular inhibitory amino acid transporter.When GABA binds to its receptors in the brain, it leads to hyperpolarization of neurons, making them less likely to fire. This action helps to "slow down" neuronal activity, providing a calming effect on the brain and helping to prevent conditions such as anxiety and seizures. It is this balance that is disrupted when the function of GABA or the enzymes that regulate its levels, like GABA-transaminase, are compromised.
The Function of GABA-Transaminase
The ABAT gene's instructions for GABA-transaminase are vital. This enzyme helps to break down GABA once it has served its purpose in neural inhibition. Without this breakdown process, GABA levels could become excessively high, disrupting the balance of neural signals.GABA-transaminase plays a pivotal role in maintaining the balance of GABA within the brain. GABA's principal function is to inhibit neuronal activity, ensuring that brain cells do not become overly excited by too many signals. This inhibitory action is crucial in maintaining the delicate balance of excitation and inhibition within the cerebral cortex, which is necessary for normal brain function.
Targeting ABAT by ASO in epilepsy
Decreasing ABAT (GABA transaminase) can potentially decrease epilepsy by increasing GABA levels in the brain. GABA is a neurotransmitter that plays a crucial role in inhibiting neuronal activity, which can help reduce seizure frequency and severity. By increasing GABA levels, ABAT inhibition may help to:
Enhance GABA-mediated inhibition: Elevated GABA levels can strengthen the inhibitory effects of GABA on neurons, making it more difficult for seizures to occur.
Reduce seizure propagation: Increased GABA can also help to reduce the spread of seizure activity by inhibiting the excitatory neurons that contribute to seizure propagation.
Improve seizure control: By enhancing GABA-mediated inhibition and reducing seizure propagation, ABAT inhibition may help to improve seizure control and reduce the frequency and severity of seizures
Conclusion
The ABAT gene is fundamental in the intricate network of the brain's chemical messengers. By providing the blueprint for GABA-transaminase, ABAT ensures that GABA's action in the brain is tightly regulated, preventing over-inhibition or excitation. This fine-tuned regulation of GABA is essential not just for maintaining calm and order within the neural circuits but also for preventing severe neurological disorders like seizures.
In summary, the ABAT gene and the GABA-transaminase enzyme are indispensable for neural health, underscoring the importance of genetic and enzymatic balance in brain function. Understanding these processes opens the door to potential therapeutic approaches for managing conditions arising from their dysregulation.
Understanding Doxorubicin: How Chemotherapy Affects Heart Health
Megha Gupta
Research Assistant, exRNA Therapeutics
Chemotherapy, a potent weapon in the fight against cancer, often comes with a double-edged sword. While it targets malignant cells, it can also affect healthy tissues, leading to adverse side effects. Doxorubicin, a widely used chemotherapy drug, is notorious for its potent anticancer effects but is also associated with a significant risk of cardiotoxicity. In this blog, we delve into the complexities of doxorubicin-induced cardiotoxicity, exploring its mechanisms, clinical implications, and potential strategies for mitigation. Doxorubicin-induced cardiotoxicity primarily manifests as cardiomyopathy, a condition characterized by the deterioration of the heart muscle. Several mechanisms contribute to this adverse effect: Oxidative Stress: Doxorubicin generates free radicals and reactive oxygen species (ROS) within cardiac cells, leading to oxidative stress. This oxidative damage disrupts cellular structures and impairs cardiac function. Mitochondrial Dysfunction: Doxorubicin interferes with mitochondrial function, disrupting energy production and triggering apoptosis (cell death) pathways within cardiomyocytes. DNA Damage: By intercalating with DNA strands and inhibiting topoisomerase II activity, doxorubicin induces DNA damage in cardiac cells, further contributing to cell death and dysfunction. Calcium Overload: Doxorubicin disrupts calcium homeostasis within cardiomyocytes, leading to calcium overload and subsequent impairment of contractile function.The cardiotoxic effects of doxorubicin can manifest acutely during treatment or emerge years after completion of therapy. Patients receiving high cumulative doses or those with pre-existing cardiovascular risk factors are particularly vulnerable. Clinical manifestations of doxorubicin-induced cardiotoxicity include:
1. Left Ventricular Dysfunction: Doxorubicin can lead to a decline in left ventricular ejection fraction (LVEF), resulting in heart failure.
2. Arrhythmias: Cardiac arrhythmias, including ventricular tachycardia and fibrillation, may occur due to doxorubicin-induced electrical disturbances in the heart.
3. Pericardial Disease: Doxorubicin can cause inflammation of the pericardium (pericarditis) or fluid accumulation around the heart (pericardial effusion).
4. Long-Term Cardiovascular Events: Survivors of doxorubicin therapy are at increased risk of long-term cardiovascular events, including heart failure, myocardial infarction, and premature cardiovascular death.
Efforts to mitigate doxorubicin-induced cardiotoxicity focus on minimizing cardiac injury while preserving its anticancer efficacy. Several strategies are employed in clinical practice:
1. Cardioprotective Agents: Co-administration of cardioprotective agents such as dexrazoxane, which chelates iron and scavenges free radicals, has shown efficacy in reducing doxorubicin-induced cardiotoxicity without compromising its anticancer effects.
2. Monitoring and Surveillance: Regular monitoring of cardiac function through imaging modalities such as echocardiography or cardiac MRI allows for early detection of cardiotoxicity, enabling timely intervention.
3. Treatment Modification: Dose optimization, schedule adjustments, or alternative chemotherapy regimens may be considered in patients at high risk of cardiotoxicity.
4. Lifestyle Interventions: Lifestyle modifications, including diet, exercise, and smoking cessation, can help mitigate cardiovascular risk factors and improve overall cardiac health in cancer survivors.
Doxorubicin-induced cardiotoxicity poses a significant clinical challenge in the management of cancer patients. Understanding the underlying mechanisms and implementing appropriate mitigation strategies are essential for optimizing treatment outcomes while minimizing cardiac morbidity. Continued research efforts aimed at elucidating novel therapeutic targets and refining cardiac monitoring strategies are crucial for improving the long-term cardiovascular health of cancer survivors receiving doxorubicin-based chemotherapy.
Harnessing the potential of RNA therapeutics presents a promising avenue for addressing cardiotoxicity induced by agents like doxorubicin. RNA-based approaches offer a versatile toolkit for targeted intervention, capable of modulating gene expression and cellular processes implicated in cardiac injury. For instance, small interfering RNA (siRNA) can be designed to silence genes involved in oxidative stress, mitochondrial dysfunction, or inflammation, thereby attenuating the cascade of events leading to cardiotoxicity. Additionally, messenger RNA (mRNA) therapies hold the potential to replenish or enhance the expression of cardioprotective proteins, bolstering the heart's resilience against chemotherapy-induced damage. Moreover, RNA-based strategies can be finely tuned to target specific cell types within the heart, minimizing off-target effects and maximizing therapeutic efficacy. As research in RNA therapeutics continues to advance, the prospect of leveraging these innovative approaches to mitigate cardiotoxicity and safeguard cardiac health holds immense promise for the future of cancer care.
ExRNA therapeutics is working on antisense oligonucleotides therapy to treat cardiovascular diseases. ASO therapy reduces the injuy of heart which was seen in the preclinical studies. It was seen that the biochemical parameters LDH, CKMB, MDA were increased in induction, catalase, GDH, T3 and T4 were decreased and type1 and 2 collagen were increased in the induction model indicating the injury of the heart, after treatment with ASO it was seen that LDH, CKMB, MDA were decreased, catalase, GSH, T3 and T4 were increased and type 1 and 2 collagen was decreased , this resulted in recovery of the injured heart proving ASO to be an efficient therapy for various cardiovascular diseases.
Enhancing ASO Specificity with BROTHERS Technology
Md. Mahfooz Khan
Research Assistant, exRNA Therapeutics
Antisense oligonucleotides (ASOs) are short, synthetic strands of DNA or RNA designed to bind to specific RNA targets and modulate their function. However, off-target binding, where ASOs interact with unintended RNA or proteins, can lead to side effects. To address this, scientists have developed the BROTHERS (BRO) technology, which uses a peptide nucleic acid (PNA) strand to improve the specificity of ASOs.
Steps to Improve Target Specificity:
Design the BRO Complex: Start with your original ASO sequence designed to target a specific RNA. Next, design a PNA strand that is partially complementary to the ASO, forming a BRO complex. This PNA strand will hybridize with the ASO, partially binding to it.
Static Control Mechanism: The BS binds to the ASO, straightening its structure and hiding some of its nucleobases. This reduces the ASO’s ability to non-specifically bind to unintended RNA or proteins, as the PNA-occupied region cannot hybridize with unintended sequences.
Dynamic Control Mechanism via Toehold-Mediated Strand Displacement (TMSD): Incorporate a toehold domain in the ASO design, a short single-stranded region at the end of the ASO that initiates binding to the target RNA. When the ASO encounters its target RNA, the toehold domain binds first, providing a strong initial interaction. This triggers a strand displacement reaction, where the target RNA displaces the BS from the ASO, allowing the ASO to fully hybridize with the target RNA.
Science Behind It at the RNA Level:
Specificity through Toehold Interaction: The toehold region ensures that the initial binding is highly specific to the target RNA sequence, reducing the likelihood of the ASO interacting with non-target RNAs.
Strand Displacement: Once the toehold domain binds to the target RNA, the rest of the ASO binds more strongly and displaces the BS. This allows the ASO to form a stable and specific duplex with the target RNA, ensuring it remains bound to the target RNA and not to off-target sequences.
Reduction of Off-Target Effects: The BS-PNA helps to structurally modify the ASO, reducing its ability to engage in off-target interactions. The PNA stabilizes the ASO in a conformation that is less prone to binding non-specific RNA sequences or proteins. The dynamic displacement ensures that even if the ASO initially binds to an off-target sequence, it can be easily displaced if it encounters the correct target RNA.
Implementation:
Synthesize the BRO Complex: Use solid-phase synthesis to create the ASO and PNA strands. Design the ASO with an appropriate toehold region that can initiate specific binding to the target RNA. Use in vitro assays to validate the target specificity and reduced off-target effects of the BRO complex.
Designing the ASO:
Suppose your ASO sequence targeting LIMK1 mRNA is 5'-AUGCUAGCUAGCUUAC-3'. Choose a segment at one end of the ASO to act as the toehold region. For instance, let the toehold be 5'-UAC-3' at the 3' end of the ASO. The rest of the ASO sequence will then be 5'-AUGCUAGCUAGC-3'.
Designing the Brother Strand (PNA): The PNA should be partially complementary to the ASO, leaving the toehold region free. Design the PNA to be complementary to the 5'-AUGCUAGCUAGC-3' segment of the ASO, resulting in the PNA sequence 5'-GCTAGCTAGCAT-3'.
Forming the BRO Complex: The PNA binds to the complementary segment of the ASO, forming a partially duplex structure that leaves the toehold region 5'-UAC-3' exposed.
Working Mechanism:
In the Absence of Target RNA: The BRO complex (ASO + PNA) remains stable, with the PNA binding to the ASO and masking its central region. This minimizes off-target interactions because the PNA-occupied region of the ASO cannot hybridize with unintended RNA sequences.
In the Presence of LIMK1 mRNA: The LIMK1 mRNA has a complementary sequence to the ASO, including a sequence complementary to the toehold region 5'-UAC-3'. When the BRO complex encounters the LIMK1 mRNA, the toehold region initiates binding due to its high affinity for the complementary LIMK1 mRNA sequence. This initial toehold binding destabilizes the interaction between the ASO and PNA, allowing the ASO to fully hybridize with the target mRNA sequence.
Summary:
By designing a PNA that is partially complementary to your ASO and including a toehold region, you can ensure that the ASO will specifically bind to the LIMK1 mRNA. The toehold-mediated strand displacement mechanism enhances specificity by allowing the ASO to interact strongly with the target mRNA while reducing off-target interactions. This approach leverages the dynamic interaction between the ASO, PNA, and target mRNA to achieve high specificity and minimize side effects.
Unlocking the Potential of ADAR Inhibitors: A Promising Future in Cancer Therapeutics
Lubnaa Firoz
Research Assistant, exRNA Therapeutics
In recent years, the field of cancer research has witnessed a surge in interest towards targeting RNA editing as a potential therapeutic strategy. Central to this endeavor is Adenosine Deaminase Acting on RNA (ADAR), a pivotal enzyme involved in RNA editing, which has emerged as an attractive target for cancer therapy.
Tumor-Suppressive Effects: ADAR can act as a protector against cancer in some cases. It does this by making specific changes to the genetic instructions carried by RNA. These changes can lower the levels of proteins that fuel cancer growth. Additionally, ADAR can modify the structure of RNA, which helps in stopping the production of proteins needed for cancer cell growth and spread.
Tumor-Promoting Effects: However, when ADAR isn't working correctly, it can lead to problems. In cancer cells, abnormal ADAR activity can create edited versions of proteins that actually help cancer to grow, spread to other parts of the body, and resist treatment. This abnormal activity of ADAR is associated with negative outcomes such as tumor progression, spreading to other parts of the body (metastasis), and resistance to drugs used in cancer treatment.
The Promise of ADAR Inhibitors: ADAR inhibitors hold promise as a novel approach to cancer therapy by targeting the dysregulated RNA editing process. By inhibiting ADAR activity, these inhibitors aim to disrupt the aberrant RNA editing patterns observed in cancer cells, potentially restoring normal gene expression and sensitizing tumors to existing treatments.
Exploring the Therapeutic Potential of ADAR Inhibitors in Cancer
Introduction: The correlation between ADAR activity and RNA editing dysregulation with cancer progression, metastasis, and drug resistance has sparked interest in exploring ADAR inhibitors as a potential therapeutic avenue. By selectively inhibiting ADAR activity, researchers aim to modulate the RNA editing landscape in cancer cells, potentially disrupting key oncogenic pathways.
PI3K/AKT/mTOR pathway
MAPK/ERK pathway
Wnt/β-catenin pathway
Notch signaling pathway
Apoptosis pathways
TGF-β signaling pathway
Current Landscape: Despite the significant findings, there are currently no FDA-approved ADAR inhibitor drugs. However, efforts to develop such inhibitors have gained momentum in recent years. Small-molecule inhibitors, such as 8-azaadenosine (8-aza-A) and 8-chloroadenosine (8-Cl-A), have shown promise in suppressing ADAR activity in various cancers. While 8-aza-A targets the catalytic domain of ADAR enzymes, preventing their interaction with RNA substrates, 8-Cl-A reduces ADAR expression. Nonetheless, a recent study has highlighted the non-specificity of these small molecules for ADAR.
Novel Approaches in Targeting ADAR Editing Activity
Antisense Oligonucleotides (ASOs):
ASOs are one approach to inhibit ADAR editing activity.These molecules specifically bind to ADAR transcript targets.Binding leads to the suppression of RNA editing by ADAR.
Duplex RNA Substrate Mimic Strategy:
Another RNA-based strategy has emerged.It utilizes a duplex RNA substrate mimic of ADAR.This mimic contains the adenosine analog, 8-azanebularine (8-aza-N).
Enhanced Potency with 8-aza-N:
Although 8-aza-N alone doesn't inhibit ADAR activity.Its incorporation into a duplex RNA structure enhances the potency of the inhibitor.
Conclusion:
The development of ADAR inhibitors as cancer therapeutics represents an exciting frontier in cancer research. Targeting the dysregulated RNA editing process through ADAR inhibition has the potential to disrupt oncogenic pathways and sensitize cancer cells to existing treatments. While there is still much to be learned and refined in this field, the progress made thus far highlights the therapeutic promise of ADAR inhibitors. Continued research and clinical investigations will pave the way for the realization of RNA editing-targeted therapies, bringing new hope to cancer patients in the future. Apart from academic labs, a number of biotech companies are also actively involved in the development of ADAR inhibitors for cancer therapy. A few notable examples are Boston-based Accent Therapeutics and Covant Therapeutics, which just recently signed a collaboration with Boehringer Ingelheim.
Understanding RNA G-Quadruplexes and Impact of Spermine on ASO Therapies
Md. Mahfooz Khan
Research Assistant, exRNA Therapeutics
Introduction: RNA G-quadruplexes (GQs) are stable structures formed by sequences rich in guanine, a building block of RNA. These structures are important in many biological processes, but understanding how they form and behave in the presence of other molecules is crucial for both basic biology and potential medical applications. This blog explores how a molecule called spermine affects G-quadruplexes, with key findings and implications explained in straightforward terms.
Spermine-Induced Aggregation:
Spermine can cause G-quadruplexes made of three-tiered guanine-rich sequences to aggregate, but it doesn’t have the same effect on two-tiered sequences at concentrations found in cells. Adding just one more guanine to a two-tiered structure can make it aggregate in the presence of spermine. These aggregates form at body temperature and are sensitive to the amount of salt in the environment.
Prokaryotic vs. Eukaryotic Conditions:
Aggregation didn’t happen under conditions similar to those in simpler organisms like bacteria, which lack spermine and have higher salt levels. The specific conditions under which G-quadruplexes aggregate suggest that these structures could play unique roles in cells, potentially affecting how genes are regulated and how certain therapies work.
Potential Effects of Spermine on Antisense Oligonucleotide (ASO) Therapies:
Stabilization and Binding Affinity: Spermine's ability to stabilize G-quadruplex structures can have implications for ASO therapies. By enhancing the stability of these RNA structures, spermine may hinder the ability of ASOs to bind to their target RNA molecules effectively. This reduced binding affinity could compromise the ASOs' ability to silence genes, impacting the overall therapeutic outcome.
Aggregation Effects: Spermine's presence may lead to the aggregation of RNA molecules. These aggregates can impede the accessibility of ASOs to their target RNA, thereby diminishing their efficacy in gene silencing. The formation of RNA aggregates induced by spermine could present a significant barrier to the successful delivery and action of ASO therapies.
Alteration of ASO Pharmacodynamics: Spermine's interactions with ASOs can result in alterations to their molecular structure. Such changes may impact the ASOs' ability to adopt the necessary conformation for effective RNA binding. Consequently, the altered pharmacodynamics of ASOs influenced by spermine could compromise their ability to interact with target RNA molecules and exert their therapeutic effects.
Influence on Cellular Uptake: Spermine's ability to neutralize the negative charges of ASOs can facilitate their entry into cells by reducing repulsive interactions with the cell membrane. However, this beneficial effect on cellular uptake may be offset by the potential for spermine-induced aggregation of ASOs. Aggregated ASOs may have reduced bioavailability, limiting their ability to reach intracellular targets and exert therapeutic effects.
Effects on RNA Degradation: Spermine-induced stabilization of G-quadruplex structures may protect RNA molecules from degradation by nucleases. This protection against RNA degradation could counteract the intended effects of ASOs designed to degrade specific RNA targets. The prolonged stability of RNA molecules influenced by spermine may interfere with the efficacy of ASO-mediated gene silencing, posing challenges for therapeutic intervention.
Summary:
Positive Effects: Spermine helps ASOs get into cells by reducing negative charges and forming compact structures. It also protects ASOs from breaking down outside cells, ensuring they reach their target.
Negative Effects: Spermine can cause ASOs to clump together, making it harder for them to enter cells. Aggregates might trap ASOs outside cells, reducing their effectiveness. Additionally, large aggregates could cause immune reactions or toxicity, affecting the safety of ASO therapies.
Understanding these dynamics is crucial for developing effective RNA-targeted therapies and for comprehending how RNA structures behave in living organisms.
Maternal-Fetal Landscape: Balancing Valproic Acid's Therapeutic Potential and Developmental Risks
Ankita Sharma
Research Assistant, exRNA Therapeutics
Introduction
Prioritizing the health of both mother and baby during pregnancy is essential, and this means examining every detail of maternal care, including medication choices. Valproic acid, a drug often used to treat epilepsy and bipolar disorder, has drawn significant attention because of its potential effects on fetal development.
Understanding Valproic Acid
Valproic acid, marketed under brand names like Depakene and Depakote, is a versatile pharmaceutical compound crucial in managing various neurological and psychiatric conditions. As an anticonvulsant and mood-stabilizing agent, this medication has proven to be an effective tool in the treatment of epilepsy, bipolar disorder, and even migraine prevention.
The mechanism of action behind valproic acid's therapeutic prowess lies in its ability to stabilize the electrical activity of neurons within the brain. By regulating this delicate neuronal balance, the medication effectively prevents the onset of seizures and helps to mitigate the disruptive mood swings associated with conditions like bipolar disorder.
Valproic Acid's Impact on Pregnancy
Prenatal exposure to valproic acid poses significant risks to fetal development, including neural tube defects like spina bifida, autism spectrum disorder (ASD), cognitive impairments, congenital malformations (e.g., heart defects, cleft palate), developmental delays, behavioral problems (e.g., ADHD), and other neurological issues (e.g., motor coordination deficits).
Unraveling the Autism-Valproic Acid Connection: A Perilous Pregnancy Puzzle
Autism spectrum disorder is a multifaceted neurodevelopmental condition characterized by diverse challenges in social interaction, communication, and behavioral patterns. The etiology of ASD is multifactorial, involving a complex interplay between genetic predispositions and environmental influences, including prenatal exposures. Emerging research has established a noteworthy correlation between in-utero exposure to valproic acid and an increased incidence of ASD.
Molecular Mechanisms: Valproic Acid's Impact on Fetal Neurodevelopment
Valproic acid's unique ability to traverse the placental barrier grants it direct access to fetal brain development, exerting a profound impact on neural developmental pathways. This pivotal exposure disrupts the delicate balance of neurodevelopment, potentially precipitating neurodevelopmental disorders like Autism Spectrum Disorder (ASD).
Comorbidity
Research has revealed a striking comorbidity between autism spectrum disorder (ASD) and allergic disorders like psoriasis, linked to shared inflammatory pathways involving the cytokine IL-17A. This convergence of inflammatory pathways may be rooted in the common embryonic origin of neural and epidermal tissues from the neuroectoderm. This shared susceptibility of the brain and skin to neurotoxic insults suggests fundamental interconnections between the neuropathology of ASD and the pathogenesis of psoriasis.
Conclusion
In maternal healthcare, meticulous medication choices are crucial for maternal and fetal well-being. Valproic acid, vital in treating neurological conditions, requires scrutiny due to its potential impact on fetal development. Its diverse therapeutic applications highlight its significance, but its prenatal effects include severe risks like neural tube defects, autism spectrum disorder, cognitive impairments, and more. Understanding the link between valproic acid and neurodevelopmental disorders reveals the importance of informed decision-making in clinical practice. Healthcare practitioners must prioritize patient education and evidence-based care to optimize outcomes for both mother and baby during pregnancy.