Gomorron, jag hinner inte ta det här på Svenska just nu… ni får köra google translation 😉 så häftigt nu händer det grejer!!! *)(* Marie
Read below to read how Dr. Fred Kaplan, Dr. Josef Kaplan and Dr. Eileen Shore have developed a new genetic approach to specifically block the damaged copy of the FOP gene in cells while leaving the normal copy untouched.
Genetic Technology Restores Normal BMP
Signaling and Suppresses Bone Cell
Differentiation in a Human Stem Cell Model of
FOP: Proof-of-Principle for the Treatment of
Frederick S. Kaplan, MD
Josef Kaplan, PhD
Eileen M. Shore, PhD
In the most direct and stealth-like approach yet to the treatment of FOP, scientists at the
Center for Research in FOP and Related Disorders at the University of Pennsylvania have
developed a new genetic approach using small sequences of ribonucleic acid (RNA) to
specifically block the damaged copy of the FOP gene in cells while leaving the normal
Every human being has two copies of the ACVR1/ALK2 gene in every cell in their body.
Individuals with FOP have one normal copy and one damaged copy of the gene in each
cell – a dangerous occurrence that causes over-activity of ACVR1 and that tips the scales
to renegade bone formation, the dreaded consequence of FOP.
Using inhibitory RNA designed and engineered to specifically silence the damaged copy
of the gene rather than the normal copy (a process known as RNA interference or RNAi),
the scientists restored the cellular function that was deranged by the FOP mutation by
virtually ridding the cells of the damaged, mutant, and dangerous ACVR1/ALK2 mRNA.
The cells were essentially left with only normal copies of ACVR1/ALK2 mRNA, thus
adjusting the cellular activity to normal. The tremendous advantage of this approach is
that ACVR1/ALK2 activity is not abolished in the cell, but brought to more normal
levels, similar to that of cells without the FOP mutation.
Imagine identical twin pilots of a commercial jet airplane. The twins are both in the
cockpit. For all outward appearances, they look identical and behave identically.
However, one of the twins is a good pilot and the other is a terrorist. What distinguishes
them is one letter in a simple instruction on how to fly the airplane, tattooed on each of
And, as in all of genetics, the instructions are written in code words of three letters each.
The good twin’s tattoo says: “Now fly the jet.” The tattoo of the terrorist twin says: “Now
fry the jet.” Just one letter difference, but the fate of the plane hangs on that one letter.
The new approach developed by members of the Penn FOP research team use allele-
specific (twin specific) inhibitory RNA designed to recognize the one letter difference in
the tattoos, and eliminate the evil twin so that the good twin can fly the airplane without
danger or interference. After the preemptory stealth attack by the allele-specific
inhibitory RNA (that identifies and knocks-out the evil twin terrorist pilot) the plane is
left with only one pilot, but a good responsible pilot. All is well!
In a landmark paper published in the Thursday October 20, 2011 online edition of Gene
Therapy (a Nature journal), Dr. Josef Kaplan (lead author), Dr. Frederick Kaplan, and
Dr. Eileen Shore (senior author), all from the FOP Research Laboratory of the Perelman
School of Medicine at The University of Pennsylvania, describe in detail this new stealth-
like proof-of-principle approach for treating FOP.
FOP is a rare genetic disorder of progressive heterotopic ossification for which there is
presently no cure. FOP is caused by a recurrent activating mutant of ACVR1/ALK2, a
bone morphogenetic protein (BMP) type 1 receptor that occurs in all classically affected
individuals. Individuals who have FOP harbor one normal copy and one damaged copy
of the ACVR1/ALK2 gene in each cell. The FOP mutation (in one of the two copies of
ACVR1/ALK2) increases BMP signaling to greater than normal levels and initiates the
formation of a disabling second skeleton of heterotopic bone.
In their study, the authors generated specific inhibitory RNA duplexes capable of
suppressing the expression of the mutant copy of the gene in connective tissue progenitor
cells from FOP patients (while leaving the normal or good copy untouched) and
importantly show that this approach decreased the elevated BMP signaling in FOP cells
to levels observed in control cells. The cells used in the experiments were adult stem (or
progenitor) cells obtained directly from discarded baby teeth of FOP patients and thus
contained the exact combination of damaged and normal ACVR1/ALK2 receptors found
in all classically affected FOP patients worldwide. The discarded teeth were obtained
from FOP pediatric patients and normal controls in the ongoing “FOP Good Tooth Fairy
While the approach outlined in this landmark study provides proof-of-principle for the
use of allele–specific inhibition of ACVR1/ALK2 in the treatment of FOP, the in vivo
utility of this approach must be confirmed in mouse models of classic FOP prior to its
consideration for human use. Additionally, other hurdles stand in the way of human
application at the present time, most notably safe delivery of the small RNA duplexes to
cells in the human body. “We have a long way to go,” acknowledge the investigators,
“but we have taken a big first step.”
Improvements in RNAi design are advancing at a rapid rate and will enhance the
stability, potency, and specificity of the inhibitory RNA allowing for long-term
experiments both in vitro and in vivo. The new RNA interference approach developed by
the Penn scientists can be applied to emerging mouse models of FOP providing hope for
a novel therapeutic strategy to decrease and perhaps eliminate the catastrophic
heterotopic bone formation in FOP patients.
This work was supported in part by the International Fibrodysplasia Ossificans
Progressiva Association, the Center for Research in FOP and Related Disorders, the Ian
Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research,
the Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine, and by
grants from the Rita Allan Foundation, and the U.S. National Institutes of Health (NIH