Angelman Syndrome – Pubmed Research for this Genetic Disease

A mother asked if I had any ideas on how to help her child with Angelman syndrome

I have summarized my research here

what is Angelman Syndrome

Angelman syndrome is a genetic disorder that causes various physical and neurological symptoms. The syndrome is characterized by developmental delays, speech impairments (with little to no language development), movement or balance problems, and a typically cheerful, bright personality with frequent laughter or smiling.

The cause of Angelman syndrome usually lies in defective or absent function of the UBE3A gene on chromosome 15. In most cases, the syndrome is caused by a deletion or mutation of the maternal chromosome 15, while the UBE3A gene originating from the father is normally inactive due to a process known as genetic imprinting.

Symptoms and severity can vary, but in addition to the above features, sleep disturbances, seizures, and a specific facial structure may also occur. There is currently no cure for Angelman syndrome, but a range of therapies and supports can help manage symptoms and improve quality of life for those affected. These include physical therapy, occupational therapy, speech therapy, and seizure control measures.

what does the UBE3A gene do?

The UBE3A gene encodes a protein known as E3 ubiquitin-protein ligase. This ligase plays an essential role in ubiquitination, a process in which ubiquitin, a small protein, is attached to other proteins. This tagging with ubiquitin serves several purposes, including degradation of the tagged protein by the proteasome, regulation of protein activity, and localization of proteins within the cell.

In the context of the nervous system, particularly in the brain, the function of UBE3A is particularly critical. It helps maintain neuronal health and function by regulating the levels of certain proteins important for brain development, synaptic plasticity (the ability of synapses to change in strength and efficiency), and neuronal signaling.

In Angelman syndrome, the loss or impairment of the maternal UBE3A gene results in the corresponding protein not being present in sufficient quantities in certain brain regions. Because the paternal UBE3A gene is normally silenced due to genetic imprinting in these regions, loss of the maternal gene cannot be compensated for, leading to the neurological and developmental problems characteristic of Angelman syndrome.

could the autophagy inducer spermidine help?

Spermidine, a naturally occurring polyamine found in various foods such as nuts, aged cheese, mushrooms and whole grains, has a variety of biological functions including promoting cell autophagy. Autophagy is a cleansing process by which cells break down and recycle damaged components, contributing to cell health and longevity.

The connection between spermidine and the UBE3A protein is of particular interest in the context of the regulation of autophagy and possibly in the treatment of neurological disorders such as Angelman syndrome. Although direct studies specifically examining the effects of spermidine on UBE3A or its role in Angelman syndrome may be limited, there are some general mechanisms by which spermidine could potentially exert neuroprotective effects:

1. **Promoting Autophagy:** Spermidine can stimulate autophagy in cells, which promotes the degradation and disposal of defective proteins and organelles. This process may be particularly important for cells that depend on the UBE3A protein to function properly, helping to maintain cell health and prevent cell death.

2. **Neuroprotection:** By increasing autophagy, spermidine can help prevent the accumulation of harmful proteins in the brain, which plays a role in various neurodegenerative diseases. Although Angelman syndrome is not considered a neurodegenerative disease in the classical sense, the spermidine-induced autophagy process may still have supportive effects by promoting neuronal function and survival.

3. **Potential Therapeutic Approaches:** Research into spermidine and other substances that affect autophagy could open new therapeutic opportunities for a variety of conditions, including genetic and neurological disorders. The precise effects of spermidine on specific genetic pathways wiHowever, the UBE3A is an area of active research.

In summary, spermidine’s potential as a neuroprotective substance is promising, particularly in view of its ability to promote autophagy. Further research is needed to understand the specific effects of spermidine on UBE3A and its potential role in treating or supporting conditions such as Angelman syndrome.

300 studies, that’s nothing

could methylfolate help?

Methylfolate, the biologically active form of folic acid (vitamin B9), plays an important role in the human body, particularly in DNA synthesis, repair and methylation, as well as in the synthesis of neurotransmitters. It is a crucial factor in cell division, growth and production of new cells and also has a significant function in the nervous system, including brain development and function.

In relation to Angelman syndrome, although there is no direct evidence that methylfolate specifically affects the symptoms or the underlying genetic aspects of the syndrome, its role in neurological functions and developmental processes could theoretically be supportive:

1. **Neurotransmitter Synthesis:** Methylfolate is involved in the synthesis of serotonin, dopamine and norepinephrine, important neurotransmitters that influence mood, learning and memory functions. Given the neurological challenges faced by individuals with Angelman syndrome, optimized neurotransmitter synthesis could potentially have supportive effects.

2. **Neural Health and Development:** Through its role in DNA synthesis and cell division, methylfolate may help support neuronal development and health maintenance. Although this does not specifically address the genetic effects caused by Angelman syndrome, adequate supplies of methylfolate could support general neuronal function.

3. **Genetic methylation processes:** Methylfolate plays a central role in methylation processes that are important in regulating gene expression. Although Angelman syndrome is specifically related to the dysfunction or loss of the UBE3A gene, a healthy methylation environment could theoretically support general gene regulation and function.

Nevertheless, there are currently no specific guidelines on the use of methylfolate as a treatment for Angelman syndrome, and scientific research in this area is limited. Care for individuals with Angelman syndrome typically requires a multidisciplinary approach tailored to the individual’s specific symptoms and needs, including but not limited to physical therapy, occupational therapy, speech therapy, and medical treatment for seizures.

It is always important to discuss the use of supplements or dietary changes with a healthcare provider, especially for those with specific health conditions such as Angelman syndrome, to ensure that these measures are safe and appropriate.

75 studies, actually nothing – but some of them show methylfolate deficiency in Angelmann syndrome –> see my article on cystic fibrosis

Which strategies are currently being researched to carry out epigenetic reprogramming (e.g. to activate the 2nd allele)

Epigenetic reprogramming is a promising approach in biomedical research, particularly for the treatment of genetic disorders such as Angelman syndrome, where activation of the inactive allele (typically the paternal allele in this disorder) represents a potential therapeutic strategy. Epigenetic reprogramming aims to change gene expression without changing the DNA sequence itself. Here are some of the strategies used in epigenetic reprogramming research:

### 1. CRISPR/Cas9-assisted epigenome editing
This technology makes it possible to target specific parts of the genome and make epigenetic modifications without changing the DNA sequence. By attaching epigenetic editors to the CRISPR/Cas9 system, researchers can activate or repress specific genetic loci. This could theoretically be used to activate the silent paternal UBE3A gene in Angelman syndrome patients.

### 2. Transcription factor-based approaches
Some research approaches focus on developing artificial transcription factors orto modify existing ones in order to specifically activate the expression of certain genes. These factors can be designed to bind to specific DNA sequences and promote transcription of the target gene, which could enable activation of a previously inactive allele.

### 3. RNA interference (RNAi) and antisense oligonucleotides (ASOs)
These molecules can modulate gene expression at the post-transcriptional level by degrading the mRNA of specific genes or blocking their function. Although this method is primarily used for gene repression, more advanced techniques could be developed to indirectly increase the expression of specific genes, for example by targeting repressor proteins.

### 4. Small molecules and drugs
Small molecules that target specific epigenetic modifiers such as DNA methyltransferases or histone deacetylases (HDACs) can be used to modify the epigenetic profile of genes. Such substances could promote activation of the inactive allele in genetic disorders such as Angelman syndrome.

### 5. Gene therapy
Although traditional gene therapy approaches aim to introduce a functional gene into cells, newer approaches could use epigenetic reprogramming to modify the expression of the endogenous gene rather than introducing an external copy.

Challenges and future prospects
While these strategies are promising, they still face significant challenges, including the precision of gene editing techniques, safety, efficiency of gene expression, and long-term effects on the cells and organism. However, research in this area is evolving rapidly, and advances are continually being made that will hopefully lead to effective therapies for Angelman syndrome and other genetic disorders.

Which small molecules are being researched to help epigenetic reprogramming

Research on small molecules relevant to epigenetic reprogramming, particularly in the context of activation of the inactive allele in genetic diseases such as Angelman syndrome, is focused on a number of targets. These molecules often target components of the epigenetic machinery, such as DNA methyltransferases, histone deacetylases (HDACs), and other enzymes involved in modifying histones or DNA to influence gene expression. Here are some classes of small molecules being studied in research:

### 1. HDAC inhibitors
HDAC inhibitors can increase histone acetylation, which leads to a more open and active chromatin structure and may promote gene expression. These molecules have the potential to activate transcription of genes that have been silenced by deacetylation.

### 2. DNA methyltransferase inhibitors (DNMT inhibitors)
DNMT inhibitors can reduce DNA methylation, a process typically associated with gene silencing. By reducing methylation, these inhibitors can promote the expression of genes that have been epigenetically repressed.

### 3. Histone methyltransferase inhibitors
These molecules target specific enzymes responsible for histone methylation, another mechanism that helps regulate gene expression. Inhibition of these enzymes can alter the epigenetic landscape and lead to the activation of certain genes.

### 4. Bromodomain inhibitors
Bromodomains recognize acetylated histones, and their inhibitors can prevent transcription factors and other regulatory proteins from binding to chromatin. This can influence gene expression and offers another starting point for epigenetic reprogramming.

### 5. SIRT inhibitors
Sirtuins are a class of HDACs that are dependent on NAD+. Inhibitors of sirtuins, similar to other HDAC inhibitors, could influence chromatin structure and modulate the expression of certain genes.

### Specific examples for research
In the context of Angelman syndrome, for example, there are studies on small molecules that aim to non-specifically activate the silenced UBE3A gene on the paternal chromosome. An example of this is research on topoisomerase inhibitors, which have shown that they can increase UBE3A expression in preclinical models.

It is important to note that the development and use of these small molecules is complex and requires careful research to evaluate their effectiveness and safety. Research in this area is dynamic and constantly evolving with the aim of finding new therapeutic options for Angelman syndrome and other genetic disordersto find information.

SIRT inhibitor resveratrol

yes, 300 studies only but that are consistently positive

Bromodomain inhibitors

which ones are there besides JQ1?

In addition to JQ1, a well-known inhibitor of the BET (bromodomain and extra-terminal) protein family, which plays a key role in the regulation of gene expression, there are several other bromodomain inhibitors that are being investigated in research and partly in clinical trials. These molecules aim to block the recognition of acetylated histones by bromodomains, which influences the recruitment of certain transcription factors to chromatin, thereby modulating gene expression. Here are some examples of bromodomain inhibitors besides JQ1:

### 1. I-BET151 (GSK1210151A)
I-BET151 is a selective inhibitor of the BET family that has been shown in preclinical studies to be effective in various disease models, including cancer and inflammatory diseases.

### 2. OTX015/MK-8628
OTX015, also known as MK-8628, is another BET inhibitor that has been studied in clinical trials for the treatment of certain types of cancer. It shows potential in inhibiting the growth of cancer cells.

### 3. CPI-0610
CPI-0610 is a BET inhibitor being studied in clinical trials for the treatment of hematology and solid tumors. It aims to modulate the expression of genes important for the growth and survival of cancer cells.

### 4. RVX-208
RVX-208, also known as apabetalone, specifically targets the BET bromodomains and has been particularly investigated in cardiovascular disease research and as a potential therapeutic agent for the treatment of atherosclerosis.

### 5. GSK525762 (I-BET762)
GSK525762 is another BET bromodomain inhibitor being studied in preclinical and clinical trials for the treatment of various types of cancer, including blood cancers and solid tumors.

These inhibitors are part of a growing class of compounds that have the potential to revolutionize the treatment of diseases in which dysregulation of gene expression plays a role. It is important to note that the development of bromodomain inhibitors is still an active area of research, and many of these compounds are in various stages of preclinical and clinical development. The safety, efficacy and therapeutic potential of these inhibitors need to be further validated through extensive clinical studies.

These are all unauthorized experimental agents