Understanding the Science behind Angelman Syndrome will help illustrate how close we are to a cure.
Angelman Syndrome is unique in many ways.
Angelman Syndrome is unique because it is caused by loss of function of a single gene rather than many genes and the gene is known – UBE3A. UBE3A is located on Chromosome 15. Each human being inherits a copy of Chromosome 15 from each of their parents. That means we each have a pair of UBE3A genes – a paternal copy from our father and a maternal copy from our mother.
Scientists have a solid understanding of the role that UBE3A plays in the body. The UBE3A gene produces Ubiquitin-protein ligase E3A which is essential to learning. In the brain, this enzyme allows for “neuron plasticity” which means it allows for neurons to bend and link together to form the pathways essential in learning. Without Ubiquitin-protein ligase E3A, one cannot learn.
The gene UBE3A is itself quite unique because of “genomic imprinting.” In every person, the paternal copy of UBE3A is silent – only the maternal copy is functional and actively used to produce Ubiquitin-protein ligase E3A. In children with Angelman Syndrome the maternal copy has either been mutated or is missing (via deletion or UPD). Even though their paternal copy is likely healthy, it is silent.
Genomic Imprinting Example
In this illustration you can see that both mice have a mutated gene which causes dwarfism. However, only the bottom mouse suffers dwarfism because, due to imprinting, in this case the mutated gene must be on the paternal copy to have an effect.
The implications of genomic imprinting are perhaps the most important. On one hand, it is due to this uniqueness in UBE3A that a child would even have Angelman Syndrome, however, on the other hand, it lends itself to a possible cure. Since every child carries a silent healthy paternal copy of UBE3A, unsilencing that gene would allow the brain to produce Ubiquitin-protein ligase E3A.
Scientists have developed an Angelman Syndrome mouse model. These mice lack the maternal UBE3A gene and thus, lack Ubiquitin-protein ligase E3A. Their behavior and physiological conditions are quite similar to conditions in human Angelman Syndrome individuals. Scientists have shown that reintroduction of Ubiquitin-protein ligase E3A into an Angelman Syndrome mouse model causes reversal of symptoms – the mice are able to learn and develop as a typical mouse would.
This is extremely important because it shows us that not only is the “damage” not permanent, but a cure could potentially reverse the debilitating effects of Angelman Syndrome. Tristan could learn to talk and develop as a typical person – living a fully functional life! This is such an amazing thing to hope for and that is why it is so important that we push for a cure as soon as possible!
The next step is to understand how the paternal copy is being silenced so that we can unsilence it. Just within the last few years there have been major advances in this area. Scientists now understand that the paternal copy is being “epigenetically silenced.” Essentially, there is so much activity on the active genes just upstream of UBE3A on the paternal chromosome 15 that the site is simply “too busy” for the UBE3A gene to be expressed. This is why you actually do see some very low levels of Ubiquitin-protein ligase E3A being expressed in Angelman Syndrome individuals.
A good way to look at this scenario is that our DNA is extremely active – there is a constant flow of delivery trucks (transcription enzymes) attaching to their docking station and copying genes. The copy they make becomes a protein which is used in the human body. We need the UBE3A gene to produce its protein – Ubiquitin-protein ligase E3A – but there are just too many trucks going in and out of the genes nearby! They are incidentally blocking our much needed truck from picking up its cargo!
Knowing this, a possible solution is to custom build a protein which will bind to those genes just upstream of UBE3A, preventing all those trucks from going to work there. This would allow our truck to bind and allow for UBE3A expression. Just this type of solution is now being shown to work at UCDavis and other research institutions – it is absolutely cutting edge science.
Scientists now have a variety of tools at their disposal to make this possible:
I. Zinc Finger Proteins, TARs, and CRISPr are all ways to make “custom fit” proteins with affinity to long specific stretches of DNA.
II. Delivery proteins have been created which can “carry” a desired protein from a site of injection to the brain and into the neuron.
III. Tracking proteins allow for real time imaging of the spread of the medicine throughout the cells of the body.
IV. Measurement of Ubiquitin-protein ligase E3A enzyme allows scientists to confirm successful expression of the silenced gene.
V. Behavioral scientists who specialize in mice, rat, pig and other animal behaviors can evaluate changes and determine the theoretical implications in humans.
I. Zinc Finger Proteins, TARs, and CRISPr are all ways to make “custom fit” proteins with affinity to long specific stretches of DNA.
II. Delivery proteins have been created which can “carry” a desired protein from a site of injection to the brain and into the neuron.
III. Tracking proteins allow for real time imaging of the spread of the medicine throughout the cells of the body.
IV. Measurement of Ubiquitin-protein ligase E3A enzyme allows scientists to confirm successful expression of the silenced gene.
V. Behavioral scientists who specialize in mice, rat, pig and other animal behaviors can evaluate changes and determine the theoretical implications in humans.
The above formula for a cure is very quickly becoming a reality. Scientists have shown this process to be successful in mice already. Angelman Syndrome model mice were injected with a protein with the goal of blocking the nearby genes and unsilencing the paternal UBE3A gene. It worked! Ubiquitin-protein ligase E3A was confirmed to be produced by the cells at near normal levels and behavior improved in some areas!
Zinc Finger Protein
There are still many steps that need to be taken – further trials in higher order species, analysis of findings, evaluation of possible side effects (short and long term), and hopefully the development of more feasible delivery systems are just the first of these steps.
Scientists are confident that a cure will be here soon and that gives us reason to hope. Angelman Syndrome could be the first neurogenetic syndrome cured and that would cause a renaissance in modern medicine! But we desperately need more funding to make it happen! Please help us spread the word to make this possible! Every voice and every dollar gets us closer to a cure for Angelman Syndrome!
