Anemia in the pediatric patient

CDKL5 All InVolved: Bridging Science And Community

From June 27 to 29 at the Holiday Inn Parco Dei Medici in Rome, the international congress "CDKL5 All InVolved" will be held, with about 300 participants including families, children affected by CDKL5 deficiency disorder, researchers from around the world, clinicians, and representatives of the pharmaceutical industry. The event aims to be a meeting point between the world of science and families, with the goal of building new alliances and strengthening the dialogue between those who live this reality daily and those who work to understand and fight it. The congress will be attended by 41 children and young people aged from a few months to 29 years with CDKL5 deficiency disorder, coming from various parts of the world: from the United States to Australia, from the Philippines to Japan. CDKL5 deficiency disorder is a rare genetic disease that affects both boys and girls (though the latter are more numerous) and causes severe motor and neurological development problems, including epilepsy. Most of these children cannot walk, talk, or feed themselves independently. To date, no diagnosis is given during pregnancy unless a specific and non-routine analysis is performed. It is not considered a hereditary condition, but a targeted investigation is recommended in case of subsequent pregnancies. Identifying the syndrome is often difficult, and early diagnosis can be complicated. Worldwide, approximately 1,500 cases are diagnosed. In Italy, according to the Rare Diseases Portal, there are at least 150 diagnosed patients. However, it is likely that the number of undiagnosed cases is higher due to the lack of awareness of the disease. The congress will dedicate a significant amount of time to research. Several presentations on ongoing research, conducted by international-level scientists, will be held in sessions dedicated to families and another aimed at pharmaceutical companies. Seven scientific projects by young Italian researchers will be presented and evaluated by the attending scientific committee. Confirming the importance of the event, the Loulou Foundation (https://www.Louloufoundation.Org/team.Html), one of the most active international organizations in promoting and funding research to find a cure for CDKL5 deficiency disorder, will also be present. Researchers' efforts are focusing on protein replacement therapy, which is being studied by Professor Maria Luisa Tutino of the University Federico II of Naples. The researcher has a daughter with CDKL5 deficiency disorder. Her studies were focused on rare diseases even before the birth of Elettra Yvonne (now 15 years old). She is now conducting studies on protein replacement therapy by producing the human protein in bacteria isolated from Antarctic seawater. Other research includes gene therapy - in Italy, Professor Elisabetta Ciani, associated with the Department of Biomedical and Neuromotor Sciences at the University of Bologna, is working on it - pharmacological therapy directed at microtubules, which is the heart of the Samael project, launched by the Dublin-based private company Ulysses Neuroscience Ltd and CURE5, which studies a new family of molecules, called Angel Compounds, derived from neurosteroids and designed by Professor Massimiliano Bianchi, CEO and founder of Ulysses Neuroscience Ltd. Other important areas of research include gut microbiota research - coordinated by Professor Paola Tognini of the Scuola Superiore Sant'Anna of Pisa, which demonstrates connections between gut microbiota imbalances and some neurological symptoms of CDKL5 deficiency disorder - and molecular therapy, a system to selectively reactivate the inactive X chromosome of patients, i.E., the silenced CDKL5 gene, without introducing any exogenous gene. This study is being carried out by an American physician, Professor of Neurology Kyle Fink, who, like the other named researchers, will be present at the international congress CDKL5 All InVolved. Amid moments of discussion, scientific sessions, activities for children, and support spaces, "CDKL5 All InVolved" represents a concrete example of how science, care, and community can work together to tackle a complex but not insurmountable challenge. "CDKL5 All InVolved" is an event that unites, inspires, and lays the foundation for a better future. The international congress "CDKL5 All InVolved" was organized by the association CDKL5 - Insieme verso la cura. The association was founded in 2014 by a group of parents who, in the misfortune of their children's illness, found the strength to unite and understand the importance of fundraising to support research. The president of the association is Barbara Verdirame and the board is composed of 5 other parents. The numerous fundraising campaigns undertaken over the years have allowed over 900,000 euros to be donated to various entities to support research. During the congress days, Professor Massimiliano Bianchi's Ulysses Neuroscience will perform blood samples from patients with CDKL5 deficiency disorder to analyze proteins associated with microtubule function. During the day, salivary samples will also be taken by Professor Maurizio Giustetto's team from the "Rita Levi-Montalcini" Neuroscience Department - University of Turin, as part of a scientific research project supporting the CDKL5 community. Amid moments of discussion, scientific sessions, activities for children, and support spaces, "CDKL5 All InVolved" represents a concrete example of how science, care, and community can work together to tackle a complex but not insurmountable challenge. CDKL5 is an event that unites, inspires, and lays the foundation for a better future. What is CDKL5 deficiency disorder CDKL5 deficiency disorder is a rare genetic neurological disease for which no diagnosis is given during pregnancy unless a specific and non-routine analysis is performed. The disease is currently considered non-hereditary, but a targeted investigation is recommended in case of subsequent pregnancies. CDKL5 deficiency disorder is caused by a mutation of the CDKL5 gene, which results in the absence or incorrect production of the protein of the same name. The symptoms of the disease manifest in the first months of children's lives. During this period, drug-resistant epileptic seizures begin. Some typical characteristics of the condition include the absence of language, gastrointestinal problems, stereotypies, hypotonia of the upper limbs and trunk, and difficulty learning simple skills (sitting, walking, grasping objects, etc.). Other frequent symptoms include a lack of interest in objects, sounds, and people, and the absence of a social smile. Additionally, a series of other complications not common to all can be found, such as visual deficits, scoliosis, bruxism, osteoporosis, respiratory and cardiac problems. Protein Replacement Therapy The aim of protein therapy is to replace the missing or malfunctioning CDKL5 protein with a laboratory-created version. This study appears promising as the created protein best replaces the diseased one in experimental models, restoring the maturation of neuronal precursors. Among the researchers studying it is Professor Maria Luisa Tutino of the University Federico II of Naples (Department of Chemical Sciences), who has a daughter with CDKL5 deficiency disorder, Elettra Yvonne. Professor Tutino, along with other colleagues, is conducting studies on protein replacement therapy by producing the human protein in bacteria isolated from Antarctic seawater. The bacterium on which the research is focused is Pseudoalteromonas haloplanktis TAC125, an Antarctic marine bacterium, the only host in which the CDKL5 protein is produced recombinantly. Gene Therapy Gene therapy refers to the transfer of genetic material aimed at preventing or curing a disease. In the case of genetic disorders, the therapy essentially consists of replacing the mutated gene with a "healthy" and functional copy of the gene itself. In Italy, Professor Elisabetta Ciani, associated with the Department of Biomedical and Neuromotor Sciences at the University of Bologna, is working on it, leading a research group dedicated to childhood neurological disorders, including CDKL5 deficiency disorder (CDD). Professor Ciani collaborates with institutions such as the Oregon Health & Science University (USA), the University of Düsseldorf (Germany), the University of Pisa, Turin, and the CNR, consolidating a strong network aimed at therapeutic development for CDD. Pharmacological Therapy Directed at Microtubules The heart of the new project "Samael," launched by Ulysses Neuroscience Ltd and CURE5, is a new family of molecules, called Angel Compounds, derived from neurosteroids and designed by Professor Massimiliano Bianchi, CEO and founder of Ulysses Neuroscience Ltd (https://ulysses-neuro.Ie/). These molecular compounds act directly on microtubules, fundamental components of the neuronal cytoskeleton, whose functionality is severely compromised in those with CDKL5 deficiency. "By restoring microtubule dynamics, the aim is to reactivate brain development and synaptic connectivity in CDKL5-deficient neurons," explains Bianchi. Research on Gut Microbiota Until now, therapies have mainly focused on the brain, but an unexpected breakthrough could come from a study coordinated by the Scuola Superiore Sant'Anna of Pisa (https://www.Santannapisa.It/it/news/intestino-parla-al-cervello-studio-cell-reports) and published in the journal Cell Reports. For the first time, it has been demonstrated how an imbalance in the gut microbiota (the set of bacteria that populate our intestines) plays a causal role in some neurological symptoms of CDKL5 deficiency disorder. "By modulating the gut microbiota, for example with targeted probiotics, specific diets, or even microbiota transplantation, we could be able to improve patients' quality of life and enhance the effectiveness of other therapies," explains researcher Paola Tognini, coordinator of the study. Molecular Therapy This is a system to selectively reactivate the inactive X chromosome of patients, i.E., the silenced CDKL5 gene, without introducing any exogenous gene. This study is being carried out by an American physician, Professor of Neurology Kyle Fink (https://health.Ucdavis.Edu/neurology/faculty/fink.Html). This approach is extremely complex but could reignite the healthy protein. The FDA, the American Food and Drug Administration, has authorized Dr. Fink to bring this therapy to a clinical level. Researcher Fink will be at the conference to present his work. The CDKL5 Insieme verso la cura Association The CDKL5 Insieme verso la cura association was founded by a group of parents who, in the misfortune of their children's illness, found the strength to unite and understand the importance of fundraising to support research. The president of the association is Barbara Verdirame and the board is composed of 5 other parents. The association has created the podcast "RaraMente - Viaggio intorno alla disabilità" (https://cdkl5insiemeversolacura.It/raramente/), based on the idea that a rare genetic disease does not only affect those who carry the mutation but also all the people around them. The podcast tells about disability and what it entails from the perspective of those who are not ill but are still forced to deal with the disease. The association, in collaboration with Professor Domenica Immacolata Battaglia of the Policlinico Gemelli in Rome, a specialist in Child Neuropsychiatry, has taken on the task of creating the national CDKL5 registry, a fundamental tool for collecting information on CDKL5 patients in Italy. The registry is also active in Verona, thanks to Professor Francesca Darra, a specialist in Child Neuropsychiatry at the Department of Biomedical and Neuromotor Sciences - Director of the U.O.C. Of Child Neuropsychiatry at the Integrated University Hospital of Verona (Policlinico G.B. Rossi). Since December 14, 2014, the day the association was founded, the numerous fundraising campaigns undertaken have allowed over 900,000 euros to be donated to various entities to support research. Together with other national family associations and foundations around the world, the CDKL5 Alliance was born. The main purpose of the alliance is to monitor the growth of the international CDD community (CDKL5 deficiency disorder) by building a strong bond between all existing and future organizations.

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New Treatment Target Found For CDKL5 Deficiency Disorder

Scientists at the Francis Crick Institute have found a new treatment target for CDKL5 deficiency disorder (CDD), one of the most common types of genetic epilepsy. 

CDD causes seizures and impaired development in children, and medications are limited to managing symptoms rather than tackling the root cause of the disease. The disorder involves losing the function of a gene producing the CDKL5 enzyme, which phosphorylates proteins, meaning it adds an extra phosphate molecule to alter their function.

Following recent research from the same lab showing that a calcium channel could be a target for therapy for CDD, the team has now identified a new way to potentially treat CDD by boosting another enzyme's activity to compensate for the loss of CDKL5. 

In research published today in Molecular Psychiatry, the scientists studied mice that don't make the CDKL5 enzyme. These mice show similar symptoms to people with CDD like impaired learning or social interaction. 

The researchers first identified that CDKL5 is active in nerve cells in mice but not in another type of brain cell called an astrocyte. In the nerve cells, they measured the level of phosphorylation of EB2, a molecule known to be targeted by CDKL5, to understand what happens when CDKL5 isn't produced. 

Interestingly, even in mice that don't produce CDKL5, there was still some EB2 phosphorylation taking place, which suggested that another similar enzyme must also be able to phosphorylate it.

By looking at enzymes similar to CDKL5, the researchers identified that one called CDKL2 also targets EB2 and is present in human neurons. In mice without both CDKL5 and CDKL2, the remaining EB2 phosphorylation almost fully dropped off.

The researchers concluded that, although most activity comes from CDKL5, about 15% is from CDKL2, and the remaining <5% from another enzyme yet to be identified. 

Their research suggests that increasing the level of CDKL2 in people who are deficient in CDKL5 could potentially treat some of the effects on the brain in early development. 

CDD is a devastating condition that impacts young children from birth, and we don't know a huge amount about why losing this one enzyme is so disastrous for the developing brain. Through this research, we've identified a potential way to compensate for the loss of CDKL5. If we can increase levels of CDKL2, we might one day be able to stop symptoms from developing or getting worse."

Sila Ultanir, Group Leader of the Kinases and Brain Development Laboratory, The Francis Crick Institute

The researchers are now investigating if mice without CDKL5 can be treated by stimulating their brain cells to produce more CDKL2. The lab is also working with biotechnology companies to identify molecules that increase CDKL2 for potential new medicines for CDD. 

Margaux Silvestre, former PhD student at the Crick and now postdoctoral researcher at the Max Planck Institute for Brain Research in Frankfurt, said: "Our discoveries offer fresh insights into the expression and regulation of CDKL5 in the brain. Moreover, the identification of CDKL2 as a potential compensatory enzyme provides hope for uncovering better treatments that could truly make a difference in the lives of the children with this devastating condition. This research owes its success to all the authors involved in the publication but also the unwavering support we received from the technical teams at the Crick – a big shoutout to them!"

The research was funded by the Loulou Foundation, a private foundation dedicated to the development of therapeutics and eventual cures for CDD.

Source:

Journal reference:

Silvestre, M., et al. (2024). Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular Psychiatry. Doi.Org/10.1038/s41380-024-02434-7.

Rare Disease CDKL5 Deficiency Disorder Granted WHO Disease ...

CDKL5 Deficiency Disorder (CDD) is a rare neurodevelopmental disorder resulting from loss-of-function mutations in the CDKL5 gene. Presenting first as infantile spasms within the first weeks of life which progresses to intractable epilepsy, CDD patients also display profound neurodevelopmental delay, with generalized hypotonia, impaired motor skills, and severely impaired speech and vision. CDD patients also have impaired sleep, gastrointestinal function, and respiratory issues. With an incidence of approximately 1 in 40,000 live births, CDD is one of the most common monogenic pediatric epilepsies, with several thousand patients estimated in the US and Europe alone. No therapies exist to treat the neurodevelopmental symptoms of CDD, and the epilepsy associated with CDD is poorly managed by current anti-seizure medications.

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