Transcript FOP Lecture - Spirit

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
(FOP)
Fibrodysplasia ossificans progressiva (FOP) is a rare catastrophic genetic disorder
caused by the lack of regulation of the bone morphogenic protein (BMP). Soft
connective and muscle tissue such as tendons and ligaments are replaced by bone.
Normally the skeleton is fashioned in the womb. After birth it matures and is used
throughout life. In FOP another skeleton is laid down which fuses to the existing
bones starting at the head and descending. Any trauma to soft tissue/ bones
causes the process to go bonkers. The patient feels local tenderness,
inflammation (“flare up”) and then a new bone.
Prior to 1996, patients would often submit to a biopsy of the inflamed areas
thought to be “bone tumors”. After healing of the surgical wound the area would be
completely fused to existing skeleton.
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The result of the growth of completely ossified bones outside of the skeleton
(“heterotropic” bone formation)
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constrains movement; mobility of joints lost
interferes with breathing (restriction of lung expansion) due to extra bone formation,
Interferes with, speaking (restriction of jaws, inability to open mouth),
mobility and all other activities of daily life
By age 5 and often sooner, painful fibrous nodules (tumor-like swellings) begin to appear
around the neck, back, and shoulders, usually after a traumatic fall or accident. The
nodules begin to transform into bone. These have been diagnosed in the past as “cancer”
and “tumors” which received surgery to remove them.. If the tiny bones of the middle ear
are involve the victim may become deaf.
Any trauma to the muscles of an individual with fibrodysplasia ossificans progressiva, such
as a fall or invasive medical procedures triggers episodes of muscle swelling and
inflammation (myositis) followed by rapid ossification in the injured area. Flare-ups /
ossification cycle may also be caused by viral illnesses such as influenza.
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The most famous case is Harry Eastlake who died prone in bed in 1866. The only
movement left to him was his lips. Normally you have to wire a human skeleton
together for display purposes, but not the case with Mr. Eastlake who is preserved
standing in the Mutter Museum.
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For this rare disease there are only 700 confirmed cases in the world.
The gene that causes ossification is normally deactivated after a baby’s bones are
formed in the womb, but in patients with FOP, the gene keeps working. Excess bones
are formed around joints, especially in the neck, spine, shoulders, chest, hips, and
knees.
The diaphragm, tongue, and ocular muscles are spared as well as cardiac and smooth
muscle.
The trademark symptom of FOP is a malformation of a newborn’s big toe with the great
toes short, bent, and turning inward.
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Inheritance of Fibrodyplasia Ossificans Progressiva
FOP a A genetic disease of dis-regulation of bone growth.
Is a random new mutation in the gametes. It can be inherited, but seldom is.
Most of the people who have it are too disabled to have children.
It is an autosomal dominant trait; each child has a 50% chance of inheriting. The
recessive homozygous condition has not been seen so it is likely ____ (fill in the
blank).
The faulty gene is ACVR1. Individuals with fibrodysplasia ossificans progressiva
have a missense (point) mutation in which the amino acid histidine is substituted
for the amino acid arginine at position 206 of the ACVR1 gene.
The mutation produces a faulty, mis-folded receptor protein product called Activin
which is a receptor protein in the plasma membrane of critical repair cells:
macrophages, lymphocytes and endothelial (mesenchymal) progenitor cells
Progenitor cells must receive specific biochemical signals to transform .
In this disease there is a "signaling error" to progenitor cells. Those that become
bone cells within soft tissue receive an incorrect message about which kind of cell
to become making
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What goes wrong in fibrodysplasia ossificans progressiva
A genetic disease of dis-regulation of bone growth caused by a mis-folded receptor
protein
The ACVR1 gene of chromosome 2 provides instructions for making the receptor protein
Activin which controls the growth and development of the bones and muscles, including
the gradual replacement of cartilage by bone (ossification) in young persons.
Activin is a very specific receptor that spans the cell membrane: one end of the protein
remains inside the cell and the other end projects from the outer surface of the cell.
Normally, Activin receives its signal from (inhibitory) protein, FKBP12. Because the
Activin is misfolded FKBP12 cannot combine with Activin to signal the cell to turn off
BMP (bone morphogenic protein). The regulatory mechanism is left on permanently.
BMP is produced in great quantities in these patients
Overgrowth of bone and cartilage and fusion of joints, resulting in the signs and
symptoms of fibrodysplasia ossificans results
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Gene ACVR1 Trivia
ACVR1 gene is located on chromosome 2. The cytogenetic notation is 2q23-q24.
Translation : Chromosome 2 on the “q” arm between band 23 and band 24.
Chromosomes have a long and a short arm seen during the pairing of homologous
chromosome at prophase I. At this time chromosomes, “tetrads”, appearing with their
centromeres which divide the chromosome into a long (“q”) and short (“p”) arm.
Gene ACVR1 is located on the long (“q”) arm of chromosome 2 between the bands
q23 and q24 as seen with special stains.
Getting really specific, the gene is located between base pairs 157,736,445 (1st band)
and 157,875,861 (2nd band) of the “q” or long arm.
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Medications
Corticosteroids like prednisone during the early part of a flare-up in major joint.
Corticosteroids help decrease inflammation and swelling.
NSAIDs also reduce inflammation. If you've ever taken Advil or aspirin, you've taken
an NSAID.
COX-2 inhibitors (like Vioxx, which is no longer on the market, and Celebrex) are a
particular kind of NSAID that seems to be very helpful in FOP treatment.
Aminobiphosphonates are anti-angiogenic, which means that they prevent the
formation of blood vessels, which bone tissue needs to grow. They also keep too
much bone resorption from happening by shortening the life span of osteoclasts.
You would think that decreased bone resorption would be a bad thing in FOP, but it
turns out that it seems to help people. Doctors aren't sure why.
Thalidomide is also an anti-angiogenic. It appears to modify immune system
responses and functions in a way that might help with flare-ups. To some people,
thalidomide brings to mind news stories of birth defects in the 1960s, after
doctors gave it to pregnant women to help with morning sickness. However,
thalidomide is supposed to be safe in people who aren't pregnant.
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Treatments
Retinoic acids, Accutane, Thalidomide type drugs
Thalidomides type drugs are the most teratogenic known to our medicine, so
far. But they have wonderful promise for these patients
Retinoic acid compounds profoundly inhibit the BMP induced cartilage
scaffolding, the first step in bone formation, which is very sensitive to retinoids
(remember those Thalidomide babies?). Remember, bones are already formed
in the newborn)
More wonderful is that all BMP signally pathways are not targeted, but the
screwed up signaling pathway for bone formation in FOP is. This class of drugs
can redirect cell fate decisions of the progenitor cells to a non-bone stem cell
(soft tissue fate) permanently”
Further, the effect seems to last…so patients may not have to keep taking the
drugs after effect achieved (this also happens with retinoid, accutane, for
acne).
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Outline Fibrodysplasia Ossificans Progressiva
Defintion: What is it
A genetic disease of dis-regulation of bone growth. A genetic disease of dis-regulation of bone growth caused by a mis-folded receptor
protein. It results in the growth of completely ossified bones outside of the skeleton
Cause
A rare catastrophic genetic disorder caused by lack of regulations of the bone morphogenic proteins (BMP’s). Soft connective and
muscle tissue such as tendons and ligaments are replaced by bone. (“heterotropic” bone formation)
Signs and symptoms diagnosis
In early childhood, painful fibrous nodules (tumor-like swellings) appearing around the head, neck, back, and shoulders
 constrains movement; mobility of joints lost
 interferes with breathing (restriction of lung expansion) due to extra bone formation,
 Interferes with, speaking (restriction of jaws, inability to open mouth),
mobility and all other activities of daily life
 The diaphragm, tongue, and ocular muscles are spared as well as cardiac and smooth muscle.
 The trademark symptom of FOP is a malformation of a newborn’s big toe with the great toes short, bent, and turning inward
Specific Genetic derangement
The ACVR1 gene on chromosome 2 has a missense mutation (arginine to histidine) in the gene product Activin
Activin is a crucial regulatory receptor protein which takes its place in the plasma membrane and cannot receive signals from the
inhibitory protein FKBP12. This leaves the switch to produce BMP (bone morphogenic protein) permanently on with no inhibition.
When a signal is received that soft tissue is injured the surrounding tissues are destroyed and bone is laid down.
ACVR1 trivia
“ACVR1 gene is located on chromosome 2. The cytogenetic notation is 2q23-q24. Translation : Chromosome 2 on the “q” arm
between band 23 and band 24
Current medications
Corticosteroids, NSAIDS . Decrease inflammation and swelling.
COX-2 inhibitors (Celebrex) a particular kind of NSAID that seems to be very helpful in FOP treatment.
Aminobiphosphonates are anti-angiogenic, which means that they prevent the formation of blood vessels, which bone tissue needs to
grow. They also keep too much bone resorption from happening by shortening the life span of osteoclasts.
Coming Treatments
Palovarotene A, a retinoid (2014)related to Accutane and Thalidomide, has been shown to block bone formation in a variety of mouse
models of FOP. Now undergoing controlled trials on real patients..
RNA interference. (2011) RNA molecule specifically engineered to silence the damaged copy of the FOP gene leaving the normal copy
intact. By ridding cells of the mutant ACVR1 mRNA the devastating FOP allele was silenced. Done in cell culture, not mouse models,
have to work out best route of administration, must do human trial
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RNA interference
Specially engineered RNAi’s. In 2011 Dr. Kaplan’s lab at Penn's State produced a
RNA molecule engineered to specifically silence the damaged copy of the FOP gene
rather than the normal copy -- a process known as RNA interference, or RNAi –
The scientists restored the cellular function caused by the FOP mutation by ridding
cells of the mutant ACVR1 mRNA RNA which totally silenced the devastating FOP
allele.
The other allele provides enough of the properly folded signaling protein.
Must find a way to safely deliver the RNAi’s.
-Remember: done in cell culture not mouse model. Must be tested in mice, then
permission to test in humans
- How will it be delivered? Will it be a shot, a pill, IV therapy, central line, PICC line or
implantable delivery device?
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Clementia Pharmaceuticals: Palovarotene A, a retinoid related to Accutane and
Thalidomide has been shown to block bone formation in a variety of mouse
models of FOP.
Clementia recently announced the launch of a 12-month randomized, doubleblind, placebo-controlled study of palovarotene.
The human cells used in the experiments were adult stem cells obtained directly
from discarded baby teeth donated by FOP patients. These and only these cells,
contained the exact combination of damaged and normal receptor proteins found
in all classically affected FOP patients worldwide.
The discarded teeth were obtained from FOP pediatric patients and normal
controls, usually non-affected siblings, in the ongoing "FOP Good Tooth Fairy
Program."
Problems to be worked out: It worked very well in cell culture and mice. Now it is
being tested in humans with the disease.
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iseases.info.nih.gov%3a80%2fgard%2f6445
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References
The girl who turned to stone : http://www.theatlantic.com/magazine/archive/2013/06/themystery-of-the-second-skeleton/309305/
How Can a Genetic Mutation Cause Muscle to Turn into Bone?
http://www.scientificamerican.com/article/genetic-mutation-muscle-bone/
Kaplan, F. Shore, E., Fibrodyplasia Ossificans Progressiva: Clinical and Genetic Aspects :
http://www.ojrd.com/content/6/1/80 (Orphanet Journal of Rare diseases )
http://www.ifopa.org/research/medical-articles.html Official site of the International Fibrodyplasia
ossificans progressiva association. Wealth of information for FOP suffers by FOP suffers including
the research on the latest meds and research papers ordinary people can read and understand.
Many tips on living with the disabilities. I Could have save a lot of time by going here for
information.
Genetics Home Reference: http://ghr.nlm.nih.gov/ A wonderful resource. Don’t leave biology
without awareness of this internet resource.
http://www.news-medical.net/news/20111109/New-genetic-approach-to-treat-fibrodysplasiaossificans-progressiva.aspx. New genetic approach to treat fibrodysplasia ossificans progressiva.
FOP Fact Sheet - The IFOPA http://www.ifopa.org/fop-fact-sheet.html
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The Medical Management of Fibrodysplasia Ossificans Progressiva: Current
Treatment Guidelines http://www.ifopa.org/living-with-fop-menu/docrepository/doc_download/422-the-medical-management-of-fop-currenttreatment-guidelines.html
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