Mensen vragen ons vaak wat Angelman nou precies inhoud en of er wat tegen te doen is. De tekst hier onder geeft een duidelijk beeld van wat het Angelman syndroom is en hoever de wetenschap al is.
How close are we to a Cure?(bron:curegarret.com)
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. Garrett 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!
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. 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!
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