FOP Italia Onlus

What the F.O.P is.

The Fibrodisplasia progressive ossificante (FOP) it is a rare illness autosomal dominant of the connective fabric characterized from congenital malformation of the first fingers of the foot and from ossificazione etereotopica post-native progressive to load of the soft fabrics. The ossificazione etereotopica generally in the first ten of life, after phases of spontaneous or consequent riacutizzazione to a trauma. These riacutizzazionis often as tumors are diagnosed and amiss they are characterized by big areas edematose, that provokes pain to load of the connective soft fabrics, inclusive tendons, ligaments, band and muscle-skeletal apparatus. The edemas to pre-bony level, kind those to load of the trunk, some times can spontaneously regress also. More often nevertheless the edemas have the tendency to progress through a mechanism incondrale and they form the bone mature etereotopico. Progressive episodes of oss. eter. they bring to ankylosis of all the greatest articulations of the skeleton, is axial that of the appendixes, making therefore impossible the movements. Toward the twenty years the most greater part of the patients they are forced therefore in wheelchair and they need an assistance to life to develop his/her own daily activities. The serious restrictive pathology to load of the thoracic wall puts the patients to increased risk of further problems to cardio-pulmonary level. The surgical trauma that joins to the resection of the bone etereotopico, for therapies immunizzanti in case of procedures odontoiatriche and viral infections type influence they bring her to new episodes of oss.eter. The auditory deficit of the management is a characteristic that joins to this pathology and it is poorly known.
Riacutizzazionis of the FOP are sporadic and not predictable; a notable variability intrapersonale and interpersonale it exists as it regards the speed of progression of the illness. Numerous big studies of search on the natural history of the FOP have confirmed that it is possible to prevent the onset, the duration or the gravity of a riacutizzazione of the FOP, although the characteristic progression has been described type anatomical. The rarity of the illness and the unpredictable nature of this pathology it makes extremely difficult to appraise any therapeutic intervention, done this already recognized to the beginning of 1918 by Julios Rosenstirn:
You/he/she is tried to attach the illness with a whole series of remedies and alternatives for the correction of a metabolic error; each of these interventions has been successful more or less only observed by the original author but labeled as a suit failure from other researchers. In many cases the symptoms of the illness spontaneously disappear often so that the therapeutic effect, always that a treatment has been established, you/he/she must not absolutely be confirm.
These words are true anchor in 2006 today, so much true as when is been written around 100 years ago. There is not at the present moment an effective preventive intervention or an effective treatment for the FOP. Thanks to the best knowledge of the pathology of the FOP new pharmacological strategies are emerging for today the treatment of the FOP. Then the physicians are found of forehead to an increasing number of potential medical interventions. Unfortunately the clinical experience, using these therapeutic interventions for the FOP is absolutely and in the most greater part of the cases type anecdotal.
The standard gold for all the pharmacological studies is the checked study randomizzati double Czech. Although these studies are extremely difficult to be conducted in the FOP, considering the few stricken patients, the erratic natural history of the pathology and the enormous variability intrapersonale and interpersonale of the FOP it does him that this type of sketch of search the best approach remains for however getting clear answers and absolutely not ambiguous to the most greater part of our problems, therefore the precise evaluation of that that is the real therapeutic utility. Further studies will have to consider this approach even if, as any other approach, it same it has in it some booby-traps. The great and extreme rarity of the FOP, the varying gravity and the elapsed clinical fluctuating they set notable questions in the evaluation of experimental therapies.
Another important factor that has prevented the study of an effective therapy for the FOP is the lack of a genetic animal model for this illness. The oss.eter.può to be induced an animal through injection, surgical plant or genetic overproduction of BMP. Nevertheless I/you/they are not you model natural or spontaneous animals of oss.eter. what you/they can reproduce in accurate way all the clinical characteristics of the FOP. While we are continuing the search of these models and we assiduously work for realizing them in artificial way the fastest street to the success in this extremely difficult field, you/he/she can be the identification of the genetic damage responsible of the FOP and in the attempt to reproduce that exact genetic damage in an animal model.
Purpose of this relationship is to revisit the principal classes of medicines that you are been used (and what in consideration are currently) for the treatment and the management of the patients affections from FOP, so that to furnish a perspective on the indications and side effects to the use of these medicines up to that studies checked more rigorous can be launched and their results can be valued.
Sottolineamo that this job relatively brings the experience and the opinions of the authors to different classes of medicines able to modify the syntomatologic outfit and you/he/she is intended therefore only as a guide in this so controversial area in therapeutic field. Although there is some common physical characteristics shared by every person struck by FOP there are nevertheless of the differences among the individuals that could alter the potential risks or benefits of any medicine or classes of medicines here following discussed. The decision to use or not to use a particular medicine must be takes at the end from the single patient or from his/her own physician.


THE PHYSIOPATHOLOGY OF THE F.O.P.

A new wave of knowledges on the molecular genetics, the pathology and the physiopathology of the F.O.P. you/they have furnished new potential therapeutic objectives for the medical intervention.
The cellular lines linfoblastoidi derived by patients with FOP is characterized by a “over” expression of proteins morfogenetiche of the bone type 4 (BMP4) and at the same time they are characterized by a bottom expression of the powerful antagonists BMP (what Noggin and gremlin) as answered to the stimulus BMP.
The cells F.O.P. I am not able to regulate in adjusted way the expressions of some antagonists BMP4 freed in answer to the signals of BMP4 and this determines a negative feedback in which the levels of expression of BMP4 and therefore the activity of BMP4 can result notably increased and sustainable in the condition FOP.
The oss.eter. in the FOP it begins from the childish age and you/he/she can be induced from a surgical trauma, from a lesion to load of the soft fabrics, from procedures of immunization with injections intramuscolo, injections for interventions odontoiatrici or viral pathologies type influence her. BMP4 is produced by the apparatus skeletal muscle and his/her expression you/he/she can be “upregolata” in the centers where a lesion is verified to load of the soft fabrics. In normal circumstances BMP4 intensely stimulates the expression than at least a big number of antagonists BMP. An antagonistic answer damped BMP4, after a trauma to the soft fabrics, it would allow the rapids expansion of the signal BMP4 that brings to the progressive formation of bony fabric. The growth of fabric vascular fibroproliferativo to pre-bony level that happens and that it is locally noticed in answer to the overespressione of BMP4 it would result amplified in case of antagonistic answer damped BMP4 and you/he/she could explain then the enormous bony induction that is observed during the phases of riacutizzazione of the FOP. These data of the FOP illustrate a great deal the importance of a critical equilibrium among the inductive morfogene (BMP4) and its antagonist in the formation of a system of organ ectopico and it would suggest a potential space for the development of strategy therapeuticses of the FOP founded on the antagonist BMP.
Besides, the cells FOP possess an intrinsic defect in the ability to regulate the levels of BMP4 in an ample range of events is metabolic that of the cellular cycle in vitro. In the normal cells the levels of BMP4 are tightly held under control in all the phases of the cellular cycle while in the cells FOP the concentration seems to vary in notable way instead. The incapability of the cells FOP to adequately regulate the concentration of BMP4 through the whole cellular cycle could point out a defect of base in the regulation of the mechanism of the BMP4. Alternatively, a defective gene that influences only an aspect of the mechanism BMP4 could have secondary repercussions type diffused. This would suggest that the geniuses that codify the proteins that regulate BMP4 and the receptors BMP4 and perhaps the proteins that degrade BMP4 or its receptors can be proteins that don't correctly work in the cells FOP.
An analysis of the molecular pathology of the activity recettoriale BMP on the surface of the cells FOP starts to furnish very important information in the understanding of the molecular mechanism that subtends to the first events of the patogenesi of the FOP. A more deepened knowledge of the systems of molecular regulation and genetics of the mechanisms BMP in the cells FOP will bring to a more rational therapeutic approach in this illness.

THE PATHOLOGY OF THE F.O.P.

The BMP4 attaches the cells mononucleari, it determines angiogenesi, it stimulates the fibroproliferazione (probably from cells staminali mesencimali) and it determines the apoptosi and it provokes bony induction endocondrale that the formation of mature bonelets determines and therefore bone etereotopico that goes to replace the apparatus muscle skeletal and other connective fabrics.
Patients' biopsies with lesions precocious FOP, gotten before the diagnoses definitive of FOP, you/they have shown an intense infiltrator linfocitario, to base of linfociti B and linfociti T, that are subsequently migrated in the apparatus stricken skeletal muscle. A thick death of skeletal muscular fibers is noticed in all the champions bioptici. Lesions of intermediary stadium are not microscopically distinguishable from the fibro aggressive juvenile mastosi and they show an intense reaction fibroproliferativa with notable neovascolarizzazioni and angiogenesi. The cells fibroproliferatives express notable quantities of BMP4 and smooth muscular proteins but, the exact origin of these cells is uncertain. The abundance of mastociti to level of the fabrics has been identified in every single stadium of the process of illness. The mastocitis can induce some trials understood cellulomediati the fibroproliferazione, the edema, the angiogenesi and you/they can also amplify the serious edema to load of the soft fabrics.
While the stadiums of the bony formation in the FOP tightly resemble to those some skeletal induction in the embryonic phase and to the closing of the bony cracks (fontanelle) in the period post-native there are nevertheless of the important differences. The inflammatory infiltrator of the first lesions FOP primarily has a character linfocitario, while the inflammatory infiltrator in the first phases of the closing of the first bony fractures primarily has character neutrofilo and monocitario. As further aspect that opposes among these situations there is not in partnership inflammation to the skeletal induction in the embryonic phase.
While the progression in the phase of the development of the lesions of the FOP follows the general mechanism of the infiltrator linfocitario, the death of the apparatus skeletal muscle, fibroproliferazione, angiogenesi, condrogenesi and osteogenesi, all the stadiums of the trials of the development are present however in the lesion FOP and they are visible within some days from its induction and they furnish an evidence that different parts of the lesions FOP they mature to different speed. For instance the external part of a lesion FOP has an aspect more mature and mature to a superior speed in comparison to the inside part. In reality all the stadiums of a lesion FOP are present very soon after his/her induction and every attempt to inhibit with success the process of maturation it will probably provoke the inhibition of multiple stadiums in the process of development of the illness. Then a lesion can be inhibited sooner greater it is the probability that the formation of bony fabric etereotopico can be prevented. To theoretical level the best approach would be to prevent in effective way the induction of the oss.eter.. As June Osborne of the university in the Michigan has declared in different contexts, speaking of advantages of the prevention: “the prevention is absolutely correct but nothing doesn't happen” absolutely.


THE IMPORTANCE OF THE ANIMAL MODELS FOR THE F.O.P.

The development of models suitable animals for the study of the FOP it is a phase of extremely important essential development for an effective therapeutic intervention. While other pathologies similar to the FOP is sporadically been described in the domestic cat, in the pig and in the dog, any other living animal is available as model of study. It is also in doubt if the pathologies similar FOP you observe in the dog, in the cat and in the pig is really the FOP. The obtainment of a really reliable animal model for the study of the FOP in the man, will probably happen after the discovery of the gene responsible of the FOP. One time gotten this of the attempts can immediately be made for developing a based really important animal model on the manipulation of the identical gene in the mouse.


THE SYSTEM MATRIGEL BMP4: A MODEL USEFUL ANIMAL

At the present moment the most reliable model for the induction of lesions isolated similar FOP is the recombinant human BMP4 genetically manipulated and mixed with a substance eterogena called vettrice matrigel that is injected in the muscular structures of the mouse. This continuous to be the most useful system to reproduce all the known stadiums of the oss.eter. Similar FOP. These stadiums include the infiltrator linfocitario and mastocitario, the death of the cells of the muscle-skeletal apparatus, as also the formation of lesions fibroproliferative highly angiogenetiche, the transformation of the lesions fibroproliferative in fabric cartilagineo, the calcification of the cartilage and the final substitution of the cartilage calcified with bone mature eterotopico that contains elements of the bone marrow. We have used this model to study the most precocious inflammatory events that join to the oss.eter. induced by BMP understood ivi the infiltrator linfocitario and mastocitario, the intent it was also to appraise the effectiveness of the antagonists BMP what the Noggin. The model of the matrigel recombinant BMP4 injected in the musculature of the mouse continues to be the system of extremely useful study to appraise various therapies for the FOP and with every probability it will keep on sustaining himself/herself/themselves valid up to that he will be able to develop a best model animal in base to the knowledge of the precise mutazione/mutazioni genica that causes the FOP.


THE LINFOCITIS COME I MODEL OF STUDY FOR THE FOP

The based model on the system of cellular crop of derivation linfocitaria is very important for the knowledge of the first events of molecular pathology and istopatologia of the FOP. The validity of this system of cells linfocitarie founds him on a series of observations and experimental data also gotten in the linfocitis of the FOP as in the translation of the signal BMP4 in the most remarkable cells:
I accumulate perivascolare of linfociti B and T (with following infiltrator and death of the apparatus skeletal muscle) they are the first data observable istopatologici in the FOP
signal of BMP4 that regulates the first phases of the differentiation linfocitaria
increase of the expression of BMP4 in the linfocitis of the lesions of the patient FOP
immunization of routine (activation iatrogena of the system immunitario) that it brings to oss.eter. of the apparatus skeletal muscle to level of the site of junction in the patient FOP but not in the normal controls
circulating linfocitis in the patient FOP show an alteration of the regulation of the signals BMP.
These data suggest that the linfocitis are a cellular model extremely profit and main point for the understanding of the first pathological molecular evident mechanisms and istopatologici of the FOP. The linfocitis that can be gotten in rapid and sure way by peripheral blood through a normal venous collecting can be immortalized in the laboratory and therefore used for the studies on the animals.
To be able to determine the ability of the cells linfoblastoidi FOP to induce lesions FOP we have performed a subcutaneous plant of cells linfoblastoidi, gotten from patient FOP and also from members of their family not struck by the illness, in the naked mouse atimico (a mouse with compromissione of the system immunitario that doesn't throw back the cells of different kind what those of the man). The cells of the non stricken subjects or they are not grown or you/they have formed some small masses with least evidences of answer fibrotica or angiogenica. Dramatically in contrast the cells of the patient FOP have determined solid masses similar to tumors in these experiment animals.
The evaluation istopatologica of these lesions has pointed out that the cells FOP has induced angiogenesi and answer fibrotica in the mouse guest, a similar picture as it regards the aspect to the first lesions FOP. The FOP-similar lesions induced by the cells have been submitted then to probing for the specific genetic sequenziazione of the man, that has confirmed that the cellular masses contained human cells and also cells you entertain. These results suggest that the cells of the patient FOP determine some modifications in the cellular growth e/o in the cellular differentiation and they also mime some events that are verified in the first lesions FOP. Then the plant of consequential cells from patient FOP in the naked mouse starts to furnish an useful cellular model for the study how much less than the first phases of the formation of the lesions FOP and it finally furnishes an intermediary model for the experimentation of potential medicines.


INTERACTION CELLS LINFOCITARIE-CELLS ENDOTELIALI: FIRST MARKERS OF THE INFLAMMATIONS

The migration of the linfocitis from the center intravascolare in the center really out of the cell endoteliale and of its membrane is the first event that can be noticed to microscopic level in a phase of riacutizzazione of the FOP. How the linfocitis you/they can leave the blood vases and to access the apparatus skeletal muscle whereas will a following be verified dead of the skeletal muscular cells? Integrate her of it, cellular sensors that act from molecules of signal, you/they are expressed by the most greater part of the linfocitis. Integrate her they interact with the receptors of the of it integrate of it, what the molecules of cellular adhesion that are found on the surface of the cells endoteliali and they regulate the infiltrator of the linfocitis in the solid organs what for example the muscles. Integrate her of it Alpha-4, a glicoproteina, is expressed on the surface of activated linfociti and monociti and they has a very important role in their adhesion to level of the vascular endoleties and in their following migration in different organs.
At the present moment we are studying the identity of these markers of the integrate on the cells of it linfocitarie and endoteliali in fabrics FOP that we have available. The identification of integrate specifications of it on the activated linfocitis, in the lesions FOP, could furnish an important therapeutic objective for the treatment of the first phases of the lesions with antibodies monoclinali humanized that they are pharmacologically already available.


THE SYSTEM IMMUNITARIO E THE FOP

Increasing evidences from all the environments of search point out an involvement of the system immunitario in the FOP. The presence of linfociti and mastociti in the first lesions FOP, the death of the cells muscle skeletal in partnership to the linfocitis, the riacutizzazionis after viral infections, the varying interval between the episodes of riacutizzazione and the positive answer of the first riacutizzazionis to the therapy corticosteroideas are all important pieces of a mosaic that it underlines and it would confirm an interest of the system immunitario in the patogenesi of the riacutizzazionis of the FOP. Some authors have also proposed that the aspects is clinical that pathological of the FOP they would suggest a component autoimmunitaria of the pathology, probably and perhaps a factor scatenante type autoimmune.


THE TREATMENT OF THE FOP SU PATHOLOGICAL BASE IS PHYSIOPATHOLOGIC

Probably The optimal therapy of the FOP will be based on the integrated knowledge of the molecular and cellular physiopathology of this pathology. We shortly introduce a profile of those that I/you/they are the actual knowledges.


CORRECTION GENICA

The FOP is probably a genetic illness and the final treatment prevederà the correction genica or a based approach on the bypass genico to cellular level and of the fabrics interested by the process of illness. The information most important that misses to the moment to the mosaic of the FOP it is the real identity of the gene FOP. This knowledge will immediately furnish an introspective in those that will be the more promising therapeutic approaches in the FOP and it will genetically stimulate the development of models valid animals to study the therapeutic potential of the medicines. The big part of the searches of laboratory today in action for the study of the FOP they are assembled really on this field of the search and d it is possible to retrieve relationships detailed of the work in progress in the 12° Annual Relationship of the project of search collaborated you FOP.


BONY BONE MARROW TRANSPLANT (CELLS STAMINALI)

Medical literature brings an alone case of bony bone marrow transplant coincidentale in a patient affection from miosite progressive ossificante (today known as FOP) that you/he/she has developed a serious anemia aplastica type idiopathic. The patient has thrown back the first bone marrow transplant after 160 days. Nevertheless you/he/she has been treated again with success with marrow always withdrawn by the same donor but using a different system of ricondizionamento. A follow-up incomplete twos years and a half from the second transplantation it pointed out that the patient was stable and his/her own mobility was not subsequently worsened. The patient has been lost then to the follow-up and the long-term condition of the FOP you/he/she is not therefore known to 20 years from the transplantation.
Recent progress in the search of base and in the clinical search point out that the cells staminali could constitute the base for the care of the FOP. In the biopsies of lesions FOP has been noticed the presence of cells ematopoietiche while you/he/she is being discovered that the cells staminali embryonic posts determine numerous fabrics mesentimali, understood ivi the muscle and the bone. Considering these aspects is justified to wonder if we should treat the patients affections from FOP replacing their pool of cells staminali type ematopoietico and if this substitution must have done with a bony bone marrow transplant, of peripheral blood and of blood of the umbilical cord or with a transplantation of cells staminali. To give an answer to this question, is necessary to consider as the transplantation of cells staminali you/he/she could be able to take care of the FOP, of as you/he/she could fail and to what clinical risks the patients should necessarily be exposed for having the possibility of a care through techniques of transplantation of cells staminali.


How the transplantation of cells staminali could treat with success or to take care of the FOP?

To the light of the data that you/they point out that cellular lines patients' linfoblastoidi with treated FOP and you transform with the virus Epstein-Barr they abnormally express elevated levels of RNA messenger and of proteins for BMP4 it is hypothetically possible that a cell abnormal ematopoietica as the most greater part of the linfocitis, could instigate the mechanisms fiosiopatologici of the FOP. Although there is no evidences that the leukocytes themselves secrete proteins of bony matrix, cells what fibroblasti, mioblasti, periciti and other cells mesentimali could deposit the eso bony skeleton in answer to an anomalous inductive bony signal coming from the leukocytes. If formation of bone eter.nella FOP from proteins anomalous osteogenetiche and you/he/she is produced then by the leukocytes a complete substitution of the compartment ematopoietico (therefore the apparatus that produces blood) substitution through cells transplanted staminali could permanently eliminate the cells FOP patogene. Although the genetic anomaly would be still present the patients, the cells able to express the anomaly you/they would be removed however; besides a small percentage of cells anomalous ematopoietiche immediately remained after the transplantation would be eliminated in the turn of different months thanks to the new system immunitario that originates from the transplanted cells. Then the FOP would fundamentally be taken care of by the procedure of transplantation of cells staminali.
Alternatively, if the leukocytes don't instigate the bony induction instead in the patients with FOP, the transplantation of cells staminali could be able to take care of the illness however. Today we know that the identifiable cells in the compartment of the cells staminalis inside the bone marrow and of the blood are able to determine the formation of cells endoteliali, of cells perivascolari, muscular, cartilaginee and also of nervous cells. Besides the cells transplanted staminali, withdrawn by the bone marrow, recently you/he/she is seen that they contribute to the cardiac muscular cells in the reparation of the heart attacks miocarditi and I am able to correct in way partial neurological defects after ischemia cerebrale.Quindi it is conceivable that the cells transplanted staminali could bring to improvement of the care of the FOP even if the cells patogene had been those muscular, endoteliali or of different origin of the connective fabric. In the turn of months or years the turnover of the fabric of the patient, replaced by new cells derived by the cells staminali trapiantante, it would gradually be able to reduce the load of illness to level of the connective fabric.


Because the transplantation of cells staminali would be able not to be able to take care of with success or to treat the FOP?

In this moment, even if some studies of search show that the cells staminali can produce cells of the soft fabrics beginning from numerous cellular lines, this it would seem to be a trial to low effectiveness. In vitro, less than an alone cell of the bone marrow on five million has the potential to be able to produce cells mesentimali (or rather some connective fabric) and the number of cells produced by every cell staminali mesentimale is absolutely endless. After the actual protocols of transplantations of cells staminali, only few numbers, probably less than him 0,1% of the total one of the cells mesentimali of any cellular line, can be identified as to be also the cell of derivation from the donor months or years after the transplantation of cells staminali. Then without new progress in the techniques of transplantation of the cells staminali this trial sufficiently is not effective probably in to replace the most greater part of the anomalous mioblastis that you/they react as also the most greater part of the fibroblastis, of the cells endoteliali, of the pericitis, and of other cells of the connective fabrics.
The homologous bony bone marrow transplant very often replaces all the cells ematopoietiche, therefore this approach should be able to take care of the illness. Nevertheless the exchange is not instant. Immediately after the homologous conventional transplantation it is assisted to an intense inflammatory answer to the chemotherapy or to the radiotherapy, that could make that the remaining cells anomalous ematopoietiche could activate and to instigate an oss.eter. promiscuous and catastrophic. Also after the following 6-12 months the linfocitis you entertain residual you/they could instigate the formation of bone etereotopico. While the frequency and the gravity of these episodes you/he/she should theoretically decrease after sometime, the patient could still die even for the complicanzes first that the care can be dispatched.
What that I/you/he/she am the cellular genesis of the FOP to take care of the illness through the transplantation of cells staminali it needs that the patients survive to the tall risk of the same transplantation. Besides the homologous transplantation is accompanied to a long period of therapy immunodepressiva therefore a long period of immunodeficiency during which the patients are to increased risk for viral infections, bacterial or micotiche and the patients with FOP have a serious thoracic restrictive pathology with a risk dramatically increased of pulmonary compromissione and pneumonia, also during the childish period. Besides the transplantation of the system thick immunitario recognizes the fabric of the patients as an extraneous body and in the attempt to throw back this fabric it is had the so-called one “graft-versus-host disease” illness I transplant versus guest. Globally the mortality after the homologous transplantation of bone marrow according to the techniques that are currently performed and in any situation is always however superior of 10-15%, and in some cases you/he/she can also reach 50% or also more.
Without knowing the specific cellular and molecular causes of the FOP we would be able he/she anchors to be able the true therapeutic objective of the underlying physiopathologic trial to miss. We could perform not a transplantation of cells toxic homologous staminali and to perform him/it with success in a patient, however not to be able to take care of the illness however and this sets a serious dilemma.
The transplantation of cells theoretically staminali is very interesting as I approach for the care of the FOP but you/he/she could be dangerous without some guarantee of care or some advantage.
To still increase the problem if a patient is not taken care of or you/he/she dies during the transplantation we could not even know the why the treatment is bankrupt. Without the knowledge of an anomalous gene or a cell to be followed the clinician and the patient they would almost face a very dangerous challenge comparable to the to pilot an eyes airplane bandaged without the equipment of automatic navigation. Considering that the most greater part of the patient FOP I am not really in a lethal clinical situation potentially that puts to hazard their life and that the stricken patients would be at the present moment seriously to a greater risk of transplantation morbidità and mortality the transplantation of cells staminali it highly reveals him risky.


What would it favor the therapeutic index in direction of the transplantation of cells staminali in the FOP?

Fundamentally the therapeutic index of the transplantation of cells staminali in patient FOP must have improved making to decrease the risk of the same procedure of the transplantation e/o improving the probabilities of success.
To decrease the risk derived by the procedure of transplantation different approaches I/you/they have been adopted what:
1. transplantation of cells staminali not-mieloablative that the transplantation morbidità could decrease making to decrease the degree of inflammation and favoring a progressive and gradual chimerismo
2. artificial chemical organoidi that could be used for preventing the immunodeficiency and the graft-host versus disease, the illness I transplant versus guest
3. new medicines for the prevention of the illness I transplant versus guest what the anti-granzime and reagents anti-fas as also the antibodies anti-cells dendritiche.
Increasing the probability of a therapeutic effectiveness of other side is necessary to identify the cellular agent scatenante of the FOP and naturally the same genetic defect. This will allow pre-clinical studies, even performed on a model of transplantation of cells staminali of origin eterologa in which the cells staminali of medullary derivation withdrawn from patient with FOP, you/they are transplanted in the mouse non obese diabetic with serious immunodeficiency combined, so that the model of treatment of the FOP can be studied before is performed on ample staircase clinical transplantations in the man. Then it it is necessary to still make numerous studies of search before the transplantation of cells staminali can be recommended as treatment of the FOP.


PREVENTION OF THE LESIONS

The prevention of the lesions to load of the soft fabrics and damage to the muscular apparatus as also the prevention of the falls remains the fundamental point in the treatment of the FOP. The intramuscular injections must absolutely be avoid. The only exception to this rule could be represented by the vaccinations for the influence in the elderly patients that have already had articular ankylosis but that they have a notable risk of consequential cardio-pulmonary complicanze from an infection however influence her. The normal procedures vaccinate them for the immunization against diphtheria, tetanus and whooping cough, therefore the trivalent vaccination, administered for intramuscular injection, it determines a notable risk of oss.eter. to level of the point of injection, while the trivalent vaccination measles-mumps-rosolia administered through injection subcutaneous or normal intravenous injection they don't set some meaningful risk.
The permanent ankylosis of the jaw can be violent from a least trauma to load of the soft fabrics during the normal dental cares: it is necessary to take very careful precautions in to offer cares odontoiatriche to patient affections from FOP. An excessive openings of the jaw and the intramuscular injections of local anesthesia must absolutely be avoid. The block mandibolare determines a muscular trauma and the local anaesthetic medicines they are extremely toxic for the muscle-skeletal apparatus.
The falls in the patient FOP can bring to serious lesions and riacutizzazioni. The patient FOP seem to almost have a ciclicità in their falls. A small trauma to the soft fabrics often door to serious exacerbations that determine oss.eter. and articular ankylosis. A limitation of the due mobility to a proud articular ankylosis notably the mechanisms of the equilibrium, provoke instability and determine a greater incidence of the falls.
The falls in the patient FOP can bring to serious cranial traumas, loss of the conscience, extortions as also lesions to the back and the neck. In comparison to subjects not struck by proper FOP for the incapability to use the superior limbs in to absorb the impact of the falls the patient FOP they are more easily hospitalized in the hospital after a fall and they have a permanent modification of the function following the same fall. In a group of 135 patient FOP the 67% of these have brought some falls that have determined a riacutizzazione of the illness. The use of a baschetto in the youngest patients can help to reduce the incidence of the serious cranial traumas that you/they can achieve to a fall.
The measures directed to prevent a fall have to be based on the change of the activity, an improvement of the safety in the home circle, the use of tools for the deambulazione, what a baton if possible as also the use of protections for the head. A modification of the activity to decrease the physical interaction can be also beneficial. To avoid completely situations to tall risk you/he/she can reduce the risk of the falls but however you/he/she can also jeopardize the functional level and the level of independence of the patient and you/he/she can result not acceptable for many.
To adjust the domestic environment with the purpose to reduce the falls can be based on to climb on some handrails on the steps, to fix to the floor the carpets, to remove the objects that can hamper the walk and to eliminate the irregularities of the floor understood ivi the thresholds on the output ports.
The prevention of the falls because of an inaccurate equilibrium starts with the stabilization of the deambulazione. The use of a baton and a tool for the stabilization (a deambulatore) you/he/she could improve the equilibrium in many patients. For more mobile subjects the use of a small wheels baton or of a deambulatore can improve the stability.
When it occurs a fall it immediately it is necessary to turn to the physician if he suspects a lesion to the skull; any cranial lesion has to be considered serious up to that the contrary one is not tried. Some signs and symptoms more common of serious cranial lesion I am: headache, sense of dizziness, loss of the equilibrium, sense of dizziness, weakness, is confusionale or loss of conscience. These symptoms don't often appear if not times after the trauma. The patient must have examined with a lot of attention from the sanitary personnel in the case in which he suspects a cranial trauma.


Substances anti-angiogeniche

The development and the growth of the human embryo as also the growth and the regression of the tumors depend on the control of the formation of new blood vases (angiogenesi). The angiogenesi also constitutes an absolute requisite for the fomazione and the development of the skeleton, for the recovery of the fractures and for the formation of the bone eterotopico. The first stadiums of the embriogenesi of the skeleton it highly corresponds preosee to the lesions fibroproliferative vascolarizzate observed in the FOP.L'angiogenesi, a characteristic istopatologica of relief of the lesions preossee of the FOP, and become therefore a potential target on which to assemble the therapy.
The basic factor of growth of the fibroblastis (bFGF), a factor of growth of the cell binding endoteliale the eparina, represents a stimulator of the angiogenesi in alive powerful extremamente that and resulted involved in the growth of the solid tumors. An investigation has been conducted on the level of bFGF in the patients affections from FOP to determine if this factor had involved in the formation of the lesions preossee. The levels of present bFGF in the urine are above all meaningfully elevated results the patients affections from FOP during the acute flare-ups of the pathological trial. For against not and finds some increase of the level of bFGF in the urine during the periods of quiescence of the illness. These data have suggested therefore the hypothesis that the present bFGF in the urine constitutes a biochemical marker for the flares up of the illness in the patients affections from FOP and that a base furnishes biochemistry to be able to consider a therapy anti-angiogenica in the initial stadiums of the pathological trial.
In 1992, in the laboratory of search for the FOP the Dr M. Zasloff discovers by chance the Squalamina, a substance anti-angiogenica gotten by the bodily fabrics of the Spinarolo (Squalus acanthias) that you/he/she could also be used for the FOP. The squalamina and a molecule similar to the present colestorolo in kind that it inhibits the proliferation of the cells endoteliali (cells of the blood vases) and that you/he/she has manifested a strong activity anti-angiogenica in the animals from laboratory and in the human beings. The squalamina modifies the answer of the cells endoteliali towards proteins that organize their form and structure.
Currently the squalamina not and more extracted by the sharks but you/he/she is synthetically produced under sterile conditions. In some studies preclinici him and observed that the squalamina inhibits the angiogenesi and the consequent growth of the solid tumors. Potentially stopping directly the trial angiogenico, the squalamina and able to slow down the progression of the lesions of the FOP in the muscle. A clinical study of phase was organized The of the Squalamina in the FOP that had as objective a limited group of adult patients affettti from FOP that they suffered from flare acute bony up. The initial study was drawn to appraise the safety and the effectiveness of the squalamina administered for by intravenous on the inhibition of the angiogenesi and it foresaw the enlistment of not more of 10 patient adult affections from FOP. In 2001 the study was approved from the FDA, dall Board of The University of Pennsylvania (Committee Istituzionale of Revision of the university of Pennsylvania), from The Clinical Research Center of the Hospital of the University of Pennsylvania (Center for the Clinical Search of the hospital of the university of Pennsylvania), from The Radiation Safety Board and The Clinical Studies Monitoring Unit of The University of Pennsylvania School of Medicines (You Committee for the Safety of the Radiations and the united one for the Monitoring of the Clinical Studies of the Faculty of Medicine of the university of Pennsylvania). Nevertheless because of the missed enlistment of the patients, after two years the study and is postposto from the pharmaceutical sponsor. Among the factors that have determined this decision I/you/they have been quoted the complexity of the sketch of the study, the difficulties met by the patients that they had to reach Philadelphia in the time period prescribed of 7 days by the onset of the flare up and the impossibility to enlist some children in the study because of the refusal expressed by the FDA when and is introduced the application to be able to study the medicine on his/her/their children you cut from FOP.
The objective of the therapy anti-angiogenica in the FOP and to inhibit the formation of new blood vases with the purpose to slow down or to inhibit the consequent production again plotted bony after the appearance of a new lesion. Despite the fact that the study on the squalamina has been postponed for the missed arruolamente of the patients, the angiogenesi can be potencialmente reduced to the least one with the use of medicines anti-angiogenici what the aminobisfosfonatis, the talidomide, the NSAIDses, the inhibitors of the cicloossigenasi 2 (cox-2) and the traps for the factor of the vascular growth. To the moment a lot of of these substances are the object of studies preclinici of development and studies initial clinicians of phase one.