Pan European Networks - Horizon 2020 - page 182

After reaching the so-called ‘extravascular space’, A1M goes to
work. It has three working mechanisms: 1) cleaning the free
radicals and also a special waste product molecule called haem;
2) repairing one of the most important structural molecules of the
body – collagen; and 3) it is specifically taken up by mitochondria.
The cleaning job is done by binding waste products with strong
chemical bonds and transporting them to the kidneys for
degradation and recycling of the atoms. It has been estimated that
as many as ten free radicals can be bound by each A1M molecule.
The haem group is an important part of the oxygen-transporting
molecule haemoglobin but falls off when red blood cells are
broken. The free haem groups are very toxic waste products.
A1M can bind and inactivate two haem groups at the same
time. The repair of collagen is done by A1M in the skin and
eyes, for example. Collagen makes up much of the tissue
between cells and is sensitive to oxidation by haem, free
radicals and UV irradiation.
The uptake in mitochondria is important in broken cells during
inflammation and wounding. It provides the mitochondria with a
‘shield’ of A1M that protects them from swelling and losing their
ability to produce energy. It also protects surrounding tissue
components around a broken cell from chemical damage by
mitochondrial free radical production. After performing the
cleaning and repairing tasks, A1M penetrates the blood vessel
walls again, enters the blood stream and is filtrated, removed
and degraded in the kidneys, its final destination. The A1M
lifecycle thus results in a net transport of waste products from
tissue to kidneys and also enables repair of oxidised, damaged
collagen fibrils.
A1M in treatment and prevention of diseases
Recent understanding of the physiological role of A1M has led to
the idea of using the protein as a drug to treat diseases or
medical conditions where overproduction of waste products in the
body is the main problem. Antioxidants such as vitamins C and E
have been tried many times in the past two to three decades for
various diseases, but have seldom led to good results. However,
A1M has many advantages over these, the most obvious being its
role as an inborn natural antioxidant. Thus, A1M has a natural
route of delivery and clearance in the body. The protein has a
several-fold higher capacity to bind radicals than vitamins C and
E, and in contrast to most food antioxidants, A1M ‘hides’ the
radicals, in the sense that they do not present any oxidative stress
anymore after binding to A1M. To allow initial studies of A1M as a
drug for treatment of relevant diseases, the researchers at Lund
University have developed methods to produce large amounts of
the protein outside the human body, in bacterial ‘protein factories’.
The first disease to be targeted by A1M is pre-eclampsia.
Pre-eclampsia, a disease with overproduction of
waste products
Pre-eclampsia is a disease of pregnancy that affects around 5%
of all pregnant women. The symptoms appear in the second half
of the gestation period as elevated blood pressure, hypertension
and acute kidney damage that causes leakage of proteins into the
urine. If not treated, pre-eclampsia can lead to eclampsia,
seizures, coma and death of both mother and child. There is no
cure for pre-eclampsia today, except forced delivery of the baby.
All treatment methods in clinical use are symptomatic, mostly
using antihypertensive drugs and general hospital care. The main
purpose of these measures is to prolong the pregnancy as much
as possible in order to minimise the risks to the newborn baby of
complications associated with premature birth.
It is now known that oxidative stress and free radicals in the
placenta are somehow involved as pathological factors in the
development of pre-eclampsia. The placenta functions as a filter
between mother and foetus that allows nutrients and oxygen to
pass but blocks the passage of all other cells and molecules,
including waste products from the foetus. One reason for this is to
prevent the mother’s immune system from attacking the foetus as
an unwanted invader of her organism. The oxidative stress is
believed to destroy the barrier function, and foetal molecules may
then pass over to the mother’s blood circulation.
Professor Hansson and his co-workers at the Division of Obstetrics
and Gynaecology at Lund University discovered that haemolysis
(rupture of red blood cells), leakage of foetal haemoglobin and
formation of free haem groups occur early in the pregnancy of
women that later develop the disease. These important clues led to
the hypothesis that overproduction of waste products from the red
blood cells in the placenta, in particular free radicals, oxygen and
free haem groups, is the main factor leading to pre-eclampsia.
Treatment of pre-eclampsia with A1M
A consequence of the waste product hypothesis is that the
disease can be prevented and treated by adding a drug that can
clean up the waste product. A possible candidate would be A1M.
Why aren’t the bodies of the pre-eclamptic women capable of
cleaning up the waste products themselves? Measurements of
concentrations of A1M, free radicals and haemoglobin in blood
and placentas from pre-eclamptic and healthy pregnant women
indeed show that the diseased women have higher
concentrations of A1M, as well as free radicals and haemoglobin,
as early as gestational weeks ten to 16, well before the clinical
symptoms first appear. A probable scenario is therefore that the
women develop oxidative stress early and try to fight this with
increased production of A1M. However, the baby and the
placenta grow quickly during the middle and last phases of the
pregnancy, which may explain why the inborn A1M cleaning
system is not capable of keeping up with the accelerated
production of toxic waste products.
Therefore, it should be possible to ‘help’ the maternal cleaning
system by adding extra A1M as a drug. The researchers decided
to test the effects of A1M treatment in laboratory experiments.
First, A1M was given to placentas that had been destroyed on the
lab-bench by perfusing with haemoglobin solutions. The
experiment was successful and the A1M treatment clearly
inhibited the toxic effects of haemoglobin and oxidative stress on
the placenta tissue. Among other effects, A1M completely
reversed the placenta leakage caused by haemoglobin. The
hypothesis was also tested in a pregnant sheep ‘pre-eclampsia
model’, which was previously established by other researchers.
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