Gian Piero

http://www.springerlink.com/content/v72j645405431r62/fulltext.pdf

----- Original Message -----

From: Mary-Lisa

To: FAPG

Sent: Thursday, May 31, 2007 5:50 AM

Subject: [FAPG] Arnulf Koeppen's Research Paper

All,

Dr Arnulf Koeppen's research paper, "The Dentate Nucleus in Friedreich's Ataxia - The Role of Iron-Responsive Proteins" has now been published. (Like his paper on the heart, this research was also based on my son Benj's organs.)

It can be found on the web, but it was a real pain in the butt to find, so I'm sending you the link to the pdf file: http://www.springerlink.com/content/v72j645405431r62/fulltext.pdf

If you have trouble downloading it, let me know and I can e-mail it to you.

Mary-Lisa

Alex (FA) - 23

Benj (FA) - Forever 20

Jennifer (Carrier) - 26

Rob - 31

Hugs,

Gian Piero

Source: FEDAES newsletter nr. 57 - May 2007

http://www.cienciaysalud.info/er/ataxias/bol/

Blood First Edition Paper, prepublished online March 22, 2007; DOI 10.1182/blood-2006-12-065433

Copyright © 2007 American Society of Hematology

SELECTIVE IRON CHELATION IN FRIEDREICH ATAXIA. BIOLOGICAL AND CLINICAL IMPLICATIONS

Nathalie Boddaert1, Kim Hanh Le Quan Sang2, Agnès Rötig2, Anne Leroy-Willig3, Serge Gallet4, Francis Brunelle1, Daniel Sidi5, Jean-Christophe Thalabard2, Arnold Munnich2 and Z. Ioav Cabantchik6

1 Pediatric Radiology Unit, ERM0205, 5 Pediatric Cardiology Unit, 2 Medical Genetic Clinic and Research Unit INSERM 781. Hôpital Necker-Enfants Malades and Université Paris V René Descartes, 75743 Paris Cedex 15, France. 3 U2R2M, CNRS UMR 8081, Université Paris Sud, 91405 Orsay, France; 4 Pediatric Unit, Hôpital de Montluçon, 03113 Montluçon Cedex, France, 6 Institute of Life Sciences and Charles E. Smith Laboratory of Psychobiology, Hebrew University , Jerusalem 91904 Israel

Running head: Iron chelation in Friedreich ataxia

4 To whom correspondence should be addressed at the Alexander Silberman. Institute of Life Sciences. Hebrew University, Safra Campus-Givat Ram, Jerusalem 91904, Israel. voice: +972-2-6585420; fax: 6586974 ; email: ioav@...

Summary

Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich-ataxia, decreased iron-sulphur-cluster and haem formation leads to mitochondrial iron accumulation and ensuing oxidative damage that affect primarily sensory

neurons, myocardium and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich-ataxia patients with a membrane-permeant chelator capable of shuttling chelated-iron from cells to transferrin, using regimens suitable for patients with no

systemic iron overload.

Brain MRI of Friedreich-ataxia patients compared to age-matched controls revealed smaller and irregularly shaped dentate-nuclei with significantly (p<0.027) higher H-relaxation rates R2*, indicating regional iron accumulation. A six-month treatment with 20-30mg/kg/d deferiprone applied on nine adolescent patients with no overt cardiomyopathy reduced R2* from 18.3±1.6 to 15.7±0.7msec-1 (p<0.002) specifically in dentate nuclei and proportionally to the initial R2* (r=0.90). Chelator-treatment caused no apparent haematological or neurological side-effects, while reducing neuropathy and ataxic-gait in the youngest patients.

To our knowledge, this is the first clinical demonstration of chelation removing labile iron accumulated in a specific brain area implicated in a neurodegenerative disease. The use of moderate chelation for relocating iron from areas of deposition to areas of deprivation has clinical implications for various neurodegenerative and haematological disorders.

Introduction

Tissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis (1). Liver, heart and endocrine glands are among the most affected organs in these forms of systemic iron overload (1). The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin becomes saturated, can permeate into particular cell types by unregulated mechanisms and cause labile iron pools to raise and challenge cellular antioxidant capacities (2).

However, in chronic inflammation (3) and in various genetic disorders (4), iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene (5,6), results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur-cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage (7). The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III), leads in turn to mitochondrial accumulation of labile iron (8,9) and ensuing oxidative damage in brain, heart and endocrine glands. However, the pathophysiological role of mitochondrial iron accumulation in oxidative damage found in FA (5,9) and other neurological disorders (10-13) has not been resolved.

In analogy to transfusional iron overload, histopathological and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord (10). Those and other pieces of evidence implicated labile iron in the oxidative damage and called for the use of antioxidants and/or chelators of iron as possible treatments of FA and other neurological disorders (13-18).

Initial studies with the antioxidant idebenone in FA indicated some cardioprotective effect, but no improvement in the ataxia (17). On the other hand iron chelation therapy has not been used in FA for two main reasons: a. lack of validated clinical methods for assessing the levels of accumulated iron in the brain and their accessibility to chelators and b. the risk of a chelating drug being neurotoxic and/or inducing global iron depletion in haematologically normal or mildly hypoferremic patients (19,20). However, the recent adaptation of MRI for assessing iron accumulation in liver (21) and heart of siderotic patients (22,23) and in brain (10,15,24) has offered a new possibility for in situ assessment of chelation treatment in FA and other forms of neurodegeneration (11,12) with brain iron accumulation (NBIA) (13).

In the search for candidate chelators with clinical record, we focused on membrane permeant agents that demonstrably reduced the production of reactive oxygen species (ROS) in living cells by reducing the levels of intracellular labile iron (25). In specifically selecting the

orally active Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one, DFP) in preference to other agents, we considered five essential properties for treating a condition of local rather than global iron accumulation (26): a. permeation, which endows the drug with the ability to cross

membranes, gain access to cell organelles and reduce iron-dependent free radical formation (2); b. extra-hepatic iron chelation ability, as applied to cardiac siderosis ( 22,27); c. ability to act selectively on the most accessible iron pools defined as labile iron pools (28, 29), as well as on subcellular compartments (2), without depleting transferrin-bound iron from plasma (30); d. ability to transfer iron chelated from the labile pools of cells to biological acceptors such as circulating transferrin (30) and e. ability to cross the blood brain barrier (31).

An efficacy-toxicity phase I-II open trial with DFP was performed on adolescent FA patients who have been on idebenone for several years, had normal echocardiogram but showed no improvement in brain MRI profiles or neurological indices. A treatment based on moderate chelation regimens based on oral DFP was applied with the view of reducing iron accumulated in specific brains areas, such as the dentate nuclei, and eventually ameliorating the neurological condition without adversely affecting haematological parameters.

Methods

Patients and study design.

Patients (age 14-23) were diagnosed for Friedreich ataxia (FA) by detecting the trinucleotide repeat expansion in the first intron of the frataxin gene. They were randomly selected from a population that had been treated with idebenone (10 mg/kg/day, in 3 p.o. doses) for at least two years prior to inclusion and continued antioxidant treatment during this study. The protocol used was designed so as to initiate treatment with a relatively low daily dose of DFP and application of strict criteria for suspending treatment following lack of tolerance due to neuronal, muscular or gastrointestinal discomfort or haematological changes. A group of 13 patients (4 males and 9 females), were randomly sub-selected to receive for up to six months either 20 or 30 mg/kg/d DFP (procured from Apopharm, Toronto, Canada) divided into two daily oral doses. A plan of staggered patient enrollment was applied with the view of minimizing the risk of drug toxicity Groups of three patients entered the study every two months, at 2 week intervals. Treatment was initiated with the lower dose. If tolerance to treatment with evidence of efficacy was found in 2 of 3 patients, a second group of patients enrolled with the same dose. If tolerance was found without evidence for efficacy in 2 of 3 patients, the second group of three patients enrolled with the higher dose. If intolerance developed in 1 of 3 patients, the treatment was continued with only the two others in the group. Only 9 patients completed a six month course of DFP, with brain MRI examinations performed at inclusion and at 1, 2, 4 and 6 months of treatment. As control for no DFP treatment we used 9 patients that were only on idebenone therapy. The protocol was promoted by Assistance Publique-Hopitaux de Paris, approved by the institutional ethical committee and registered at the National Health Authority (AFSSAPS) and at the International Protocol Registration System (www.clinicaltrials.gov) (study ID:NCT00224640). A written informed consent was obtained from patients and parents.

The International Cooperative Ataxia Rating Score (ICARS) was used to assess the symptoms of ataxia before and after month 1 and 6 of the study (32) with four subscales: posture and gait disturbance, kinetic functions, speech disorders and oculomotor disorders. Scores were summed to give a total score (0-100), with higher numbers indicating worse ataxia. The Perdue Pegboard test applied by the same investigator on a limited number of patients was used for assessing the speed performance, delicate movements and manipulative dexterity. The participant was asked to insert as many nails as possible into preset holes, linearly drilled into a wooden board in a limited space of time (20� with two hands, separately and together).

The risk of agranulocytosis and other potential adverse effects of DFP observed in 1% of thalassemia patients (19,26), led us to closely monitor patients for neutropenia, agranulocytosis, musculoskeletal pain and zinc deficiency which included weekly blood counts, serum iron, ferritin and transferrin concentration and renal and liver function.

MRI measurements.

Clusters of iron cause local non-homogeneity in magnetic field and therefore decrease the MRI signal of surrounding water. This leads to variations in the apparent transverse relaxation rate (R2*), or its inverse T2*, the indexes used to quantify MRI signal decay (11, 20). Assuming a homogeneous external magnetic field, changes in R2* reflect variations in local iron concentration or in deoxyhemoglobin levels due to regional changes in blood perfusion (31). MRI examinations were done on a 1.5 T Signa unit (GE Medical Systems, Milwaukee, WI, USA) using a phased array head coil. Deep grey structures were localized by using a T2*-weighted echo-planar sequence. A voxel encompassing the left and right nuclei (dimensions 6 x 3 x 2 cm3) was positioned on the largest section of dentate nuclei and its automatic shimming was performed to minimize regional magnetic field variations. For each selected section iron monitoring was performed by using a single-slice multi-gradient-echo sequence (field of view 24 cm, 255x224 matrix, slice thickness: 5mm, TR: 400 ms, ten echoes at TE from 10ms to 100 ms, flip angle: 50°, acquisition time: 3 minutes). Volume selection for shimming and single slice multi-gradient echo acquisition was repeated at the level of pallidal nuclei. The determination of R2* was performed from data of the multi-gradient echo sequences by adjusting in each pixel the Si signals obtained at echo times TEi (i = 1.10) according to the equation Si = So.exp (-R2*.TEi). A high resolution image of local R2* values was built and the mean value of R2* was calculated in various regions of interest (ROI's), by the same radiologist.

At 1.5 tesla, the image resolution attained was adequate for obtaining only a single elliptical ROI of 10 mm2 , typically placed at the center of each nucleus in order to minimize R2* variance.

MRI measurements were made twice on the same day at 2 hrs intervals. As internal control, several (2 or more, depending on the size of the region) circular ROI's of 24 mm2 were drawn in the white matter of cerebellar hemispheres posterior to the dentate nuclei, where iron

concentration is assumed to be low, and in pallidal and thalamic nuclei.

Statistical analyses.

At the basal state, R2* values in the various structures were compared using a generalised estimating equation (GEE) model, taking into account the individual levels with both the cerebral structure and the side as categorical covariates. For each cerebral structure, repeated MRI measurements over time were analysed using a GEE model with the time of measurement as factor. Individual contributions were weighted using the inverse of the variance of R2* in the corresponding region of interest. All calculations were carried out using the GEE procedure from the geepack library, R statistical package (http://www.R-project.org). A p value < 0.05 was considered significant. Tests were adjusted for multiple comparisons according to the Bonferroni’s rule. Anova (one way) and Student paired t-tests were carried out with Origin v 7.5 (Originlab Corp., Northampton MA)

Results

Changes in morphology and in iron levels in specific brain areas.

The images displayed in Fig. 1 were selected among those obtained with FA patients at the onset of chelation treatment (n=9 that completed the treatment) and among age matched adolescents that were admitted for unrelated conditions. The images highlight the morphological changes in size and shape that dentate nuclei undergo in 3 representative adolescent FA patients compared to age matched controls (Figure 1).

The mean R2* constants (in s-1) calculated for various ROI’s of a brain area of a given individual showed reproducibility (measured by the variation coefficient in repeated examinations) of 4% in dentate nuclei and 6% in cerebellar cortex. The calculated R2* values in the dentate nuclei were significantly but not substantially higher in FA than in controls (R2* =18.3 + 1.7 s-1 as compared to 16.6 ± 1.2 s-1, p<0.05) (n=9 in each group). In addition, the R2* values in FA (n=9) were relatively higher in pallidum (19.6 ± 1.9 s-1, p<0.05) than in their dentate nuclei and lower in their cerebellum and thalamus (13.9 ± 0.6 s-1, p<0.05 and 15.2 ± 2.8 s-1, p<0.05 respectively), in accordance with the relative amount of iron chemically detected in those areas in normal individuals (15, 34-36).

Unlike in a previous study (10), the increased R2* values observed in dentate nuclei of FA patients showed no correlation with age, possibly because of the small group of patients that participated in the study. The increased R2* values might reflect changes in: a. accumulation of iron as proposed earlier (10,15,24,34-36) and by analogy to what has been obtained in other organs in systemic iron overload (21-23) and b. deoxyhemoglobin levels underlying reduced blood perfusion caused in damaged brain areas (33). Although the chemical nature of the accumulated iron is not known, an iron chelator that might have access to the affected areas could be instrumental in discerning between the relative contribution of the above 2 factors and provide some insights into the nature of the local iron contributing to the R2* values. Following 20-30 mg/kg/d DFP administration to 9 FA patients, there was a significant decrease in the relaxation rate R2* in dentate nuclei from 18.3 + 1.7 s-1 at treatment onset to 16.2 ± 0.8 s-1, p<0.001) after one month, to 16.6 ± 1.3 s-1, p<0.002 after 2 months, to 16.4 ± 0.8 s-1, p<0.01 after four months and 15.7± 0.7 s-1, p<0.002) after six months of DFP administration (Fig. 2).

Although the profiles of R2* values differed among patients in the course of DFP treatment, they reached a basal level after 2-4 months. Moreover, no short-term difference was observed between the two doses of DFP (20 and 30 mg/kg/day), suggesting that maximal efficacy might apparently have been reached with the lowest dose. However, following a six-month course of treatment with DFP on 9 patients there were no morphological changes in dentate nuclei detected or any significant changes in R2* values in other sections of the brain. The respective mean ± SD of R2* values at month 0 and 6 were: 19.6±1.9 vs 19.2± 1.4 in pallidal nuclei, 15.2±1.9 vs 14.6±0.9 in thalami and 13.9±0.4 vs 13.9±0,53 in cerebellar white matter regions. A comparable group of patients treated only with idebenone for 6-12 months showed no significant change in R2* in any of the above regions of the brain, including the dentate nuclei (Boddaert and Munnich, unpublished) (Figure 2).

Analysis of R2* changes following 6 months of DFP treatment (Fig. 2) revealed that the higher the R2* at the onset of treatment the greater the decrease in R2* (Fig. 3). The relative change in R2* correlated linearly with the initial R2* value (inset of Fig. 3). Only 1/9 treated patients (with initially low R2* value) showed no significant change after six months of DFP treatment. We interpret these results as indicating that DFP chelates labile iron that specifically accumulated in dentate nuclei (Figure 3).

Changes in clinical parameters during treatment.

An initial treatment was applied on two FA patients using a DFP dose of 80 mg/kg/day (2 daily servings), which is in the therapeutic range used on thalassaemia subjects (15,16, 21) and recommended by Apopharm. The treatment was suspended after two weeks due to serious adverse reactions in one of the patients that included: fatigue, headache, nausea, dizziness, poor head control, abnormal eye movements and fluctuating consciousness. An inquiry revealed that the affected patient had been for 2 weeks on a cloroquine-proguanyl prophylactic therapy for malaria, raising the possibility of drug-drug interactions. However, as such events have not been reported in thalassemic patients receiving DFP for transfusional iron overload (19,20,26), we assume that FA patients, having no systemic iron overload, might display a lower toxicity threshold for DFP. Another possibility is that an excessively high peak level of drug is attained in plasma following oral intake of unitary doses of 40 mg/kg/d, twice a day, rather than 25 mg/kg/d doses taken thrice a day by Thalassemia patients (19).

The six month study plan was therefore redesigned and dosing limited to 20-30 mg/kg/day DFP. Of the 13 patients that entered the new protocol, 3 were withdrawn because of complaints of muscular-skeletal pain, or dizziness or Guillain Barre syndrome and 1 because of agranulocytosis that resolved afterwards. Of the 9 that completed the study, a neurological improvement was noted by parents and uninformed relatives within four weeks of treatment.

Constipation, incontinence and some subjective signs of peripheral neuropathy disappeared within two months. Limb extremities, which were cold, mottled and hypersensitive, warmed in several patients with the sensation of feeling one’s feet and floor surface again. Delicate

movements and manipulative dexterity (e.g, handwriting, keyboard typing, hairdressing, eye make-up) and speech fluency were reportedly improved in several patients (Table 1). General strength, quality of sitting, standing and facility of transfers (from bed to wheelchair or toilets)

also improved. The youngest (14 years) treated patients benefited most from the trial in term of delicate movements, balance, stability and autonomy. These observations were seemingly unbiased, as they were independently and consistently reported by the parents and/or by

supporting personnel (Table 1). They yielded modest but significant changes in ICARS scores following 6 month treatment, with the youngest patients attaining ≥10% improvement. The inclusion of patients at a higher dose of DFP (30mg/kg/day), essentially reproduced the above

observations in terms of tolerance and relative efficacy of DFP, improvement in speed of performances and dexterity (Table 1). The Perdue Pegboard test which objectively assesses the impact of the drug on manipulative dexterity was applied on 3 patients randomly selected at the onset of treatment with DFP. The mean scores fell significantly (p>0.05) from 44±7 to 35±5 following a 6 month chelation treatment (not shown).

Changes in biochemical and haematological parameters during treatment

Administration of DFP resulted in a small but significant decrease in serum ferritin levels in only two patients, but with no significant change in haemoglobin or plasma iron levels (patients C and I, Table 2). A retroactive inquiry revealed that the two patients entered the study after recovering from recent infectious episodes, possibly causing an elevated serum level of the acute-phase reactant ferritin.

Discussion

Iron accumulation has generally been taken as an indication for potential biological damage due to the propensity of the metal to evoke oxidative stress when present in labile forms (37). This has been assumed to be the case in organ iron overload resulting from the presence of high levels of LPI (2) and in various disorders in which iron accumulates in particular organs as a result of chronic inflammation (3) or disorders of cell iron metabolism (4,38). For systemic iron overload, the use of iron chelators has had an unquestionable therapeutic record, particularly in the treatment of hemosiderosis of various types (14,20,25) and more recently in preventing or reversing iron-evoked cardiac failure in thalassemia (23,27, 39). A major contribution to the recent success in the treatment of iron overload is the advent of non-invasive techniques for assessing organ iron overload that paved the road for optimizing the chelation regimens, particularly MRI measurements of iron accumulation in organs such as liver and heart (21-23).

In FA, the evidence of iron accumulation in mitochondria (5, 8, 9) was supported by studies indicating early iron accumulation in the cerebellum of patients (particularly the dentate nuclei) (10, 15). However, the pathological role of iron as a causative or exacerbating factor in

FA (5, 40) and in other neurological disorders (11-13,16) has remained a matter of debate.

Similarly controversial is the use of iron chelators for treating FA and other neurological conditions (14, 18, 41). In these diseases the proposed target of chelators is detoxification of iron accumulated in specific brain areas and for FA possibly also in the heart and endocrine

glands. However, in FA, where there are either normal or marginally lowered levels of plasma iron (42,43) it may be considered inadvisable to chelate iron needed to support iron-sulphur cluster formation (44,45), which is already impaired due to frataxin deficiency (5). The design of a chelator that is orally active, membrane permeant and capable of scavenging iron from mitochondria of specific areas of the brain, while sparing the bulk of physiologically essential iron, is a challenging task.

The present study was an initial attempt to approach that problem at the clinical level with the view of assessing by MRI the accessibility of iron accumulated in dentate nuclei of FA patients to a chelator in clinical use in iron overload at doses considered to be safe (19). The FA patients engaged in the phase I-II open label study by random selection were in the 14-23 age range, all treated for several years with the free radical scavenger and antioxidant idebenone (17, 46,47). These patients showed essentially no functional cardiac complication or abnormal echocardiograms and yet there were no indications for R2* changes in any area of the brain or neurological effects attributable to antioxidant treatment. At the onset of the study, the dentate nuclei of the nine randomly selected adolescent FA patients showed MRI-detectable alterations in shape and R2* values that were marginally but significantly different from normal individuals (Fig. 1). This reinforces the previous neuropathological observations of iron accumulation and tissue damage (10, 15), but not unequivocally, since changes in R2* in damaged brain areas could also be attributed to changes in deoxyhemoglobin concentrations due to altered blood perfusion (33). However, if the R2* value represents even in part an accumulation of iron in specific areas of the brain (e.g. the spinocerebellar and pyramidal tracts, spinal cord and dorsal root ganglia), it would mean that iron accumulation might be relatively early event in FA, since it was evident in very young patients. We reasoned that if in FA some component of R2* might be in equilibrium with labile iron forms, namely those that are redox active and potentially chelatable (25), then chelation treatment might decrease R2* values in the areas of interest and possibly confer antioxidant protection. The alternate explanation that an iron chelator might affect blood perfusion is not inconceivable, but highly unlikely.

The selection of the hydroxypyridinone Deferiprone (FerriproxR or L1) iron chelator that has been approved in Europe for treating some cases of thalassemia (19, 20, 26, 38) was based on several criteria: a. the orally active membrane-permeant iron chelator (29) efficiently removes iron from mitochondria in living cells (2, 48) and b. the chelated iron complex, deferiprone-Fe, can transfer iron to transferrin (30). This condition is satisfied as long as transferrin is not iron saturated, as is the case with FA patients (Table 1; 42) and the chelator is used at moderate doses; and c. owing to its small molecular weight and favourable chemical properties, the drug was also expected to readily cross the blood-brain barrier, as animal studies indicated (31). The selected dosage of deferiprone was 20-30 mg/kg/day, namely one fourth the daily dose used in thalassemia major (19, 20) and in the range to have experimentally no adverse effects on irondependent brain enzymes (31).

The initial purpose of this efficacy-toxicity study was to monitor chelator evoked changes in brain iron deposits using MRI, with the view of assessing the feasibility of conducting a longterm evaluation of DFP on disease progression. The selection of R2* measurements as indicators of brain iron deposits was based on the wide experience gained with MRI (15, 34-36), particularly in animal and clinical studies in which DFP demonstrably reversed the changes in heart T2* values caused by iron overload and improved cardiac ejection fraction (22,23). In FA, deferiprone given at relatively low daily doses, efficiently and progressively decreased iron accumulated in dentate nuclei in 8/9 patients, as reflected in the R2* values (Fig. 2). For most treated patients the major reduction in R2* was within two months of treatment and the larger the initial R2* value the more robust and proportional the change evoked by the chelator (Fig. 3 and inset). This would indicate that the R2* values provide a quantitative measure for chemical forms of potentially chelatable iron accumulated in the dentate nuclei. Moreover, with our knowledge of deferiprone’s ability to scavenge cell iron (2,29,48) and assuming the concentration of chelator attained in brain to be similar to that in plasma (at most 20-30 μM at peak values following a single 10mg/kg/d dose of chelator and a t½ value of 2-3 h in plasma) (26), one can deduce that the R2* in the dentate nuclei represents: a. accumulated forms of iron which are labile and directly chelatable and/or b. accumulated forms of iron (e.g. ferritin) that chelation can indirectly reduce by triggering proteolytic degradation of ferritin. Thus by binding labile iron, deferiprone might shift the equilibrium away from cell accumulated metal, as shown before by us in myeloid cells (49) and implied in recently published studies on biochemical properties of ferritin iron (50, 51). As to the chemical nature of the labile iron forms, those might be comprised of low molecular weight iron complexes (2) and/or of iron loosely bound to enzymes such as hydroxylases (31). This is in line with the observed susceptibility of frataxindeficient systems to iron-driven ROS formation and oxidative damage and their protection by iron chelators (41), but apparently not with the lack of changes in mitochondrial labile iron detected in lymphoblasts derived from FA patients (52).

A interesting observation was that, other than dentate nuclei, no other brain areas of FA patients underwent any significant change in R2* upon chelation treatment. This apparent selectivity can be explained by one or more of the following possibilities: a. the chelator has no access to areas other than the dentate nuclei; b. the forms of iron in other areas are not easily chelatable, either because they are compartmentalized or associated with degradation products of ferritin such as hemosiderin (45) or c. other factors contribute to R2* in areas outside the dentate nuclei. To our knowledge, the present study provides the first in situ demonstration of iron chelation acting in a specific area of the brain in the clinical setting.

In the present efficacy/toxicity phase I-II study there were no a priori expectations regarding clinical benefits that could be obtained in a 6 month trial period. However, particular consideration had to be given to the appearance of any adverse reactions to treatment and

especially to haematological changes that even a mild chelation treatment could evoke in FA patients that were already borderline hypoferremic-hypoferritinemic at inclusion (Table 2). As shown, the fact that 1/13 patients withdrew from the study because of agranulocytosis, 2/13 due to drug intolerance and 1/13 due to an unrelated condition, might indicate a lower tolerance to deferiprone in FA than in Thalassemia (19, 20). From Table 2 we deduced that the mild regimen of chelation used for up to 6 months on the remaining 9 FA patients was seemingly safe.

Nonetheless, despite the apparent lack of statistically significant haematological changes impaired by moderate oral chelation, we noted a trend of mild but steady decrease in blood ironassociated parameters. This calls for a close surveillance in future trials aimed at optimizing treatment.

We also noticed that a moderate chelation treatment can significantly shift the range of R2* (s-1) measured values in dentate nuclei of FA patients from 16.8-21.2 s-1 to 15.4-17.1 s-1, that is within the R2* margins determined empirically for a cohort of age-matched non-FA

subjects, similar to what has been reported earlier (10). The most substantial and statistically significant shift was attained by the 3 patients with highest initial R2* (G-I in Fig. 2). However, with present information one is not in a position to attach a therapeutic value to the chelator15

evoked shifts in R2*. For that purpose it is necessary to establish normal and pathological ranges of R2* in larger controlled studies.

This leaves open the question of whether after attaining steady R2* levels the drug treatment should be further moderated or on the other hand, whether iron reinforcement should be used as means to alleviate the mild hypoferemia-hypoferritinemia. In that respect, clinical experience (S. Gallet and A. Munnich, unpublished) showed that oral iron supplementation exacerbated ataxia symptoms in FA patients. Moreover, in vivo studies with frataxin-deficient Drosophila indicated a higher susceptibility of flies to iron-driven oxidative stress (53).

However, most importantly and particularly serendipitous, were the observations indicating improvement with respect to constipation, incontinence, manipulative dexterity, fluency of speech, some subjective signs of neuropathy and even ataxic gait (Table 1). The modest but significant changes were observed in ICARS, particularly in youngest patients.

Although these observations are of an objective nature, they could not be correlated with MRI measurements because of the small sample and short period of treatment. Therefore, results should be regarded with caution until supplemented with comprehensive placebo-controlled

studies that should address the different neuro-motor properties and cardiac function in a quantitative manner. Moreover, this open label single arm study was limited to DFP used in conjunction with idebenone, to a period of 6 months and to adolescents with a focus on brain

MRI and preliminary neuromotor functions. Therefore, it remains to be confirmed by long-term studies that should incorporate DFP alone and in combination with idebenone as well as with chelators with better safety profiles for young populations, such as deferasirox (Exjade).

The change in R2* values and ensuing clinical results of chelation provide some clues as to the pharmacological modus operandi of DFP as possible scavenger of potentially toxic iron and/or as a vehicle for bypassing frataxin underexpression and supporting ISP formation. A

possible role of idebenone in the present studies cannot be overlooked. Studies carried out in animal cell models deficient in frataxin have clearly indicated that idebenone supplementation compensates for the e-chain respiratory deficiency (41,54,55), while iron chelators rescue cells from toxic iron accumulating in mitochondria and promoting oxidative damage (14, 18, 48).

These findings have been further strengthened in frataxin-deficient yeasts that attained iron homeostasis by inducing frataxin expression (54) and overcome oxidative stress by overexpressing mitochondrial ferritin (55). In the clinical setting, raising brain erythropoietin levels by chelation-mediated activation of HIF (via prolyl-hydroxylase inhibition) (56) and thereby inducing frataxin expression (57) can be envisioned as a neuroprotective manoeuvre conferred by regional iron chelation. Such a mechanism raises the prospects of prophylactic chelation as a means to prevent impending damage by iron and for reversing iron-induced oxidative injury in at least some sensory neurones of the central nervous system, primarily at the early stages of FA and other diseases of NBIA (13).

Although this study dealt with chelation of iron accumulated in a specific brain area, it also has implications for diseases of regional iron accumulation in which relocation of iron per se might be of therapeutic value, as in the anaemia of chronic inflammation/disease (3). In that

case, a chelator-mediated transfer of iron from reticuloendothelial cells to plasma apotransferrin, as indicated in earlier chelation studies (30) might provide an artificial by-pass for the obstructed physiological iron exit-pathway associated with hepcidin-down-regulated ferroportin (58).

Acknowledgments

F. Girard (GE-Health Care Technology Europe), DRC-APHP, Association Francaise contre la Myopathie (AFM), Israel Science Foundation (ISF) and AFIRN, for partial support; Dr. Nir Navot for his interest in the work. Prof. U. Motro for statistical advice.

Author’s contributions

N. Boddaert: MRI studies, K.H. Le Quan Sang: patient coordination and lab tests: A. Rötig: lab tests: A. Leroy-Willig: computing MRI analysis, S. Gallet: pediatric hematology follow-up; F. Brunelle: MRI studies; D. Sidi: echocardiography; J.C. Thalabard: design of clinical trial and statistical analysis; A. Munnich: design and supervision of trial, data analysis and writing of paper; Z.I. Cabantchik project design, data analysis and writing of paper. AM and ZIC initiated the studies and had equal contributions.

References

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2. Glickstein H, Ben El R, Link G, Breuer W, Konign AM, Hershko, C, Nick H and Cabantchik ZI (2006). Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood 108:3195-3203.

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10. Waldvogel D, van Gelderen P, Hallett M (1999) Increased iron in the dentate nucleus of patients with Friedrich's ataxia. Ann Neurol 46:123-125

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12. Götz, M, Double, K, Gerlach, M, Youdim, MB and Riederer, P (2004).The relevance of iron in the pathogenesis of Parkinson's disease. in Redox active metals in neurological disorders. Levine SM, Connor, JR and Schipper, HM Ann. N.Y. Acad. Sci. 1012, pp. 193-198

13. Johnson, MA, Kuo, YM, Westaway, SK, Parkr, SM, Ching, KHL, Gitschier, J and Hayflick, SJ (2004). Mitochondrial localization of PANK2 and hypothesis of secondary iron accumulation in panthotenate-kinase associated neurodegeneration. in Redox active 19 metals in neurological disorders. Levine SM, Connor, JR and Schipper, HM Ann. N.Y. Acad. Sci. 1012, pp. 282-298.

14. Kalinowski, DS, and Richardson, DR (2005). The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer . Pharmacol Rev 57:547-583

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16. Connor JR. (1997) Metals and Oxidative Damage in Neurological Disorders. Plenum Press: New York.

17. Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A (1999) Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study. Lancet 354:477-479

18. Richardson DR, Mouralian C, Ponka P, Becker E. (2001). Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron. Biochim Biophys Acta. 1536:133-40.

19. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. (2003).Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 102:1583-1587

20. Franchini M, Veneri D (2004) Iron-chelation therapy: an update. Hematol J 5:287-292

21. Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, Deugnier Y (2004) Noninvasive assessment of hepatic iron stores by MRI. Lancet 363:357-362

22. Wood, JC, Otto-Duessel, M.; Aguilar, M., Nelson, MD; Coates, TD; Pollack, H. and Moats, R. (2005) Cardiac Iron Determines Cardiac T2*, T2, and T1 in the Gerbil Model of Iron Cardiomyopathy. Circulation 112:535-543.

23. Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, Gotsis ED, Tanner MA, Smith GC, Westwood MA, Wonke B, Galanello R (2006) Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic

myocardial siderosis. Blood 107: 3738-374.

24. Haacke EM, Cheng NY, House MJ, Liu Q, Neelavalli J, Ogg RJ, Khan A, Ayaz M, Kirsch W,(2005). Imaging iron stores in the brain using magnetic resonance imaging. Magn Reson Imaging. 23:1-25

25. Hershko CM, Link GM, Konijn AM, Cabantchik ZI (2005). Iron chelation therapy. Curr Hematol Rep 4: 110-116.

26. Hoffbrand AV, Cohen A & Hershko C. (2003). Role of deferiprone in chelation therapy for transfusional iron overload. Blood; 102: 17–24.

27. Hershko C, Cappellini MD, Galanello R, Piga A, Tognoni G, Masera G. (2004). Purging iron from the heart. Br J Haematol. 125:545-551

28. Cabantchik ZI, Kakhlon O, Epsztejn S, Zanninelli G, Breuer W.(2002). Intracellular and extracellular labile iron pools. Adv Exp Med Biol. 509:55-75. 20

29. Zanninelli G, Brissot P, Hider RR, Konijn AP, Shanzer A and Cabantchik ZI (1997). Chelation and mobilization of cellular iron by different classes of chelators. Mol Pharmacol. 51:842-852.

30. Breuer W, Ermers MJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI (2001) Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used for assessing chelation therapy. Blood 97:792-798

31. Waldmeier PC, Buchle AM, Steulet AF. (1993). Inhibition of catechol-o-methyltransferase (COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo. Biochem Pharmacol.

45:2417–24.

32. Cano SJ, Hobart JC, Hart PE, Korlipara LV, Schapira AH, Cooper JM (2005) International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich's ataxia? Mov Disord 20:1585-1591

33. Bandettini PA, Kwong KK, Davis TL, Tootell RB, Wong EC, Fox PT, Belliveau JW, Weisskoff RM, Rosen BR. (1997) Characterization of cerebral blood oxygenation and flow changes during prolonged brain activation. Hum Brain Mapp 5, 93-109.

34. Drayer B, Burger P, Darwin R, Riderer S, Herfkens R, Johnson GA. Magnetic Resonance imaging of brain iron (1986). Am. J. Roentgenol. 147: 103–110.

35. Schenck JF. (2003) Magnetic resonance imaging of brain iron. J. Neurol. Sci. 207: 99–102.

36. Chen JC, Hardy PA, Clauberg M, Joshi JG, Parravano J, Deck JH, Henkelman RM, Becker LE, KucharczykW. (1989) T2 values in the human brain: comparison with quantitative assays of iron and ferritin. Radiology 173: 521–526.

37. Haliwell B, Gutteridge JMC (1998). Free Radicals in Biology and Medicine, ed 3. Oxford, Oxford University Press, 1998, pp 351–429

38. Camaschella C (2005) Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 106: 3710-3717.

39. Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio, GC, Forni, GL, Gamberini, MR, Ghilardi, R, Piga, A, Romeo, MA, Zhao, H and Cnaan, A (2006). Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood.

107: 3733-3737

40. Simon D, Seznec H, Gansmuller A, Carelle N, Weber P, Metzger D, Rustin P, Koenig M, Puccio H (2004) Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia. J Neurosci 24:1987-

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41. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G. (1999. The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet. 8:425-3021

42. Wilson RB, Lynch DR, Fischbeck KH. (1998) Normal serum iron and ferritin concentrations in patients with Friedreich's ataxia. Ann Neurol. 44:132-134.

43. Wilson RB (2006). Iron dysregulation in Friedreich ataxia Semin Pediatr Neurol.13:166-75.

44. Muhlenhoff U, Gerber J, Richhardt N, Lill R (2003) Components involved in assembly and dislocation of iron-sulphur clusters on the scaffold protein Isu1p. EMBO J 22:4815-4825.

45. Grabill C, Silva AC, Smith SS, Koretsky AP, Rouault TA. (2003) MRI detection of ferritin iron overload and associated neuronal pathology in iron regulatory protein-2 knockout mice. Brain Res. 971:95-106.

46. Geromel V, Darin N, Chretien D, Benit P, DeLonlay P, Rotig A, Munnich A, Rustin P. (2002). Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab.77:21-30.

47. Hart PE, Lodi R, Rajagopalan B, Bradley JL, Crilley JG, Turner C, Blamire AM, Manners D, Styles P, Schapira AH, Cooper JM. (2005). Antioxidant treatment of patients with Friedreich ataxia: four-year follow-up. Arch Neurol.62:621-626.

48. Glickstein H, El RB, Shvartsman M, Cabantchik ZI (2005) Intracellular labile iron pools as direct targets of iron chelators: a fluorescence study of chelator action in living cells. Blood 106:3242-3250

49. Konijn AM, Glickstein H, Vaisman B, Meyron-Holtz EG, Slotki IN, Cabantchik ZI.(1999) The cellular labile iron pool and intracellular ferritin in K562 cells. Blood. 94:2128-34.

50. Jameson, G.N.L., Jameson, R.F., and Linert, W. (2004). New insights into iron release from ferritin: direct observations of the neurotoxin 6-hydroxydopamine entering ferritin and reaching redox equilibrium with the iron core Org. Biomol. Chem. 2: 2346-2351.

51. De Domenico, I, Vaughn, M.B., Li, L., Bagley, D., Musci, G., Ward, D.M. and Kaplan, J. (2006). Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome EMBO J. 25: 5396–5404

52. Sturm B, Bistrich U, Schranzhofer M, Sarsero JP, Rauen U, Scheiber-Mojdehkar B, de Groot H, Ioannou P, Petrat F. (2004). Friedreich’s ataxia: no changes in mitochondrial labile iron in human lymphoblasts and fibroblasts. A decrease in antioxidative capacity? J. Biol.

Chem. 280: 6701– 6708

53. Anderson PR, Kirby K, Hilliker AJ, Phillips JP. (2005) RNAi-mediated suppression of the mitochondrial iron chaperone, frataxin, in Drosophila. Hum Mol Genet. 14:3397-405.

54. Cavadini, P., Gellera, C., Patel, P.I. and Isaya, G. (2000) Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum. Mol. Genet., 9: 2523-2530

55. Campanella A, Isaya G, O'Neill HA, Santambrogio P, Cozzi A, Arosio P, Levi S. (2004) The expression of human mitochondrial ferritin rescues respiratory function in frataxin-deficient yeast. Hum Mol Genet. 13:2279-885122

56. Wang, GL and Semenza, GL (2003) Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor DNA 1 binding activity. Implications for models of hypoxia signal transduction. Blood 82:3610-3615

57. Sturm, B, Stupphann, D, Kaun, C, Boesch, C, Schranzhofer, M, Wojta, J, Goldenberg, H and Scheiber-Mojdehkar, B (2005) Recombinant human erythropoietin: effects on frataxin expression in vitro. Eur. J. Clin. Inv. 35: 711–717 expression in vitro. Eur. J. Clin. Inv. 35:

711–717

58. Ganz T and Nemeth E (2006). Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol 290:199-203.

http://www.cienciaysalud.info/er/ataxias/bol/

---

From: STHEPHANIE RIFFO FERNANDEZ <sthephanieriffo@...>
Reply-To: HispAtaxia@yahoogroups.com
To: HISPANO ATAXIAS <HispAtaxia@yahoogroups.com>
Subject: [HispAtaxia] PREGUNTA?
Date: Mon, 28 May 2007 05:23:18 +0200 (CEST)

HOLA CHICOS

 

MI NOMBRE ES STHEPHANIE, TENGO 22 AÑOS, SOY CHILENA Y HACE MUY POCO QUE SOY PARTE DE ESTE GRUPO, ADEMAS NO HE HABLADO MUCHO HACI QUE NO CREO QUE ME CONOSCAN.

 

APARTE DE MANDARLES MUCHOS SALUDOS Y CARIÑOS A TODOS, QUIERO PREGUNTARLES ALGO, TAL VEZ MI IGNORANCIA ES GRANDE PERO BUENO ES PARA SALIR DE ELLA QUE PREGUNTO.  EN EL POCO TIEMPO QUE LLEVO ME HE DADO CUENTA DE LA GRAN CANTIDAD DE ATAXICOS Y AF EN ESPAÑA, Y ME LLAMA TREMENDAMENTE LA ATENCION, ES SOLO CURIOSIDAD,

 

UN BESITO A TODOS

STHEPHANIE

---

LLama Gratis a cualquier PC del Mundo.
Llamadas a fijos y móviles desde 1 céntimo por minuto.
http://es.voice.yahoo.com

Gian Piero & tutti i membri di FA_babelFAmily

----- Messaggio originale -----

Da: darryboy49

A: GP

Inviato: Domenica, 27 maggio 2007 16:23 PM

Oggetto: Brevettato un nuovo sistema per il trasporto di farmaci attraverso la barriera ematoencefalica 

http://www.brni.org/news/httpwww.brni.orgnewspress-releases2007-05-22.htm

De: darryboy49

Para: GP

Enviado el: domingo, 27 de mayo, 2007 4:23 PM

Asunto: Nuevo método patentado para transportar medicamentos a través de la barrera  hematoencefálica

Nuevo método patentado para transportar medicamentos a través de la barrera hematoencefálica

Queridos amigos,

os envío la traducción de este artículo que me pareció interesante. Contacté por e- mail con la Dra. Shroff.  En su respuesta (sábado, 23 de mayo) me dice que también están trabajando en ataxia de Friedreich con éxito. Su objetivo es parar la progresión de la enfermedad, pero que de momento no hay garantías.

Con afecto,

Mari Luz González

http://www.gibconnect.com/~gibraltarldm/Stem_Cell_Cure.html

View Full Screen   Download Windows Media Player

¿Cómo lo hace?

La Dra. Shroff realiza  trasplantes de  células madre embrionarias en pacientes con enfermedades incurables. No quiere revelar la tecnología exacta pero afirma que cultiva las células madre en condiciones de laboratorio acreditadas y con diferentes líneas celulares para enfermedades específicas.

Cada tipo de enfermedad tiene un protocolo diferente y por lo tanto también un tratamiento y dosis de células madre específico. Su técnica le permite usar únicamente un embrión que le permite desarrollar un banco de células estaminales “ inagotable “ desde  su punto de vista.

¿Por qué razón no ha ofrecido sus descubrimientos a la comunidad científica para que ésta  pueda examinarlos?

La Dra. Shroff responde que ha comunicado sus descubrimientos  a las autoridades de la India y cree que mantiene todo en regla ya que se ajusta a las leyes de su país.

Pero los escépticos  en la profesión médica  la acusan de estar usando a sus pacientes como cobayas humanos y que la supuesta mejoría se debe al efecto placebo ya que no ha habido ensayos clínicos fiables.

Me he tomado la molestia de conseguir los resultados de los pacientes  tratados por la Dra. Geeta Shroff.

Thank you so much Darryboy for sharing this important news!

Gian Piero & all FA_babelFAmily members

----- Original Message -----

From: darryboy49

To: GP

Sent: Sunday, May 27, 2007 4:23 PM

Subject: New Patented Method for Transporting Medicine Across the Blood-Brain Barrier

http://www.brni.org/news/httpwww.brni.orgnewspress-releases2007-05-22.htm

New Patented Method for Transporting Medicine Across the Blood-Brain Barrier


Researchers at the Blanchette Rockefeller Neurosciences Institute have patented a new way of safely transporting medicine across the blood-brain barrier.

The blood-brain barrier is a group of cells that line the brain's blood vessels, protecting vital brain structures from foreign substances. The barrier has posed enormous difficulties for researchers who want to deliver therapeutic drugs to the brain to treat tumors, infections and degenerative brain diseases such as Alzheimer's and Parkinson's.

The new method takes advantage of a process called transcytosis, which a cell normally uses to transport necessary molecules, such as cholesterol, into the brain. In early tests, BRNI scientists were able to use the new way to deliver a variety of test substances into
the brains of rats with no ill effects.

Researchers are hopeful that this will some day be helpful to patients, according to Daniel Alkon, M.D., scientific director of BRNI.

"This may lead to a powerful new tool that clinicians can use to treat brain diseases," Dr. Alkon said. "The blood-brain barrier provides effective protection to the brain against circulating toxins, bacteria and other harmful substances. But we need to have an effective means of delivering drugs across the barrier if we are going to offer patients better treatment options."

The new method patented by BRNI is based primarily of low-density lipoproteins (LDLs), a class of molecules that naturally occur in the blood. To help the LDL particles reach their target, BRNI researchers have coated the particles with a natural protein known as
apolipoprotein E, which helps direct the particles to receptors on the blood-brain barrier cells. These receptors then assist the particle, which can contain any drug in its central lipid core, across the barrier into the brain.

According to Alkon, previous attempts to develop carriers relied on viruses and artificial polymers, which could penetrate the barrier, but posed high levels of risk. Earlier carriers, like liposomes, were unstable, or tended to rid their cargo in unwanted places - like the
liver or blood vessel linings. BRNI's system prevents lipoproteins from abandoning their cargo until reaching the target destination, ensuring that the particles are stable in the bloodstream.

U.S. patent number 7,220,833, "Artificial Low-Density Lipoprotein Carriers for Transport of Substances Across the Blood-Brain Barrier," was issued to BRNI for this development today, May 22.

BRNI (http://www.brni.org) is a non-profit research institute dedicated to study of human memory. Its primary mission is to accelerate neurological discoveries from the lab, including diagnostic tools and treatments, directly to patients who are suffering from neurological diseases such as Alzheimer's. U.S. Senator Jay Rockefeller of West Virginia founded the institute in memory of his mother, who died of Alzheimer's disease.





 

Jornadas de Convivencia

15-17 de junio de 2007

Villagarcía de Campos (Valladolid) 

España

OBJETIVOS:

• Promover las relaciones de intercambio y de convivencia.

• Dar apoyo a las familias con personas enfermas de ataxia, tratando de potenciar la ayuda mutua y las relaciones afectivas entre enfermos y familiares

• Información sobre la Ley de dependencia y los baremos aplicables

• Informar de los nuevos tratamientos farmacológicos y en qué Centros se suministran.

• Informar sobre los posibles ensayos clínicos y los resultados que en cada caso se van obteniendo.

• Informar sobre las gestiones que se están llevando a cabo ante Autoridades y Centros de Investigación, para potenciar el conocimiento de estas Enfermedades Raras, entre los Colectivos de investigadores y personal Sanitario. Centros de referencia y Ponencia en el Senado sobre las enfermedades raras.

• Informar sobre el estado actual de la investigación, y la búsqueda de terapias actuales, a través de

1. La red española de ataxias.

2. La red europea de investigación sobre ataxias dominantes.

3. Fármacos resultados obtenidos con ellos.

4. Fármacos en vías de investigación. Resultados preliminares.

5. Otras terapias.

DESTINATARIOS: Familiares y enfermos de Ataxia

PARTICIPANTES: 160 personas

ORGANIZACIÓN DE LA REUNIÓN:

Federación de Ataxias de España

Asociaciones de Ataxia pertenecientes a FEDAES

FECHAS: 15, 16, 17 de junio de 2007.

LUGAR: Monasterio San Luís Jesuitas. Villagarcía de Campos. Valladolid.

PROGRAMA

Viernes 15 de junio de 2007

13,00 Recepción y acogida

14,00 Comida

16,00 Exposición de material ortoprotésico

18,00 Tiempo libre

20,30 Cena.

22,00 Fiesta de convivencia.

Sábado 16 de junio de 2007

9,30 Desayuno

11,00 INAUGURACIÓN.

Dª Pilar Martín Iglesias. Presidenta de la Asociación de ataxias de Castilla León

D. Ignacio del Burgo: Senador, ponente de la Ponencia sobre Enfermedades raras en el Senado.

11,30 MESA 1: Investigación básica en ataxias. Modera: Dª Isabel Campos.

Dr. Francesc Palau "La ataxia de Friedreich: Resultados de las últimas investigaciones “Instituto de Biomedicina de Valencia.

Dr. Ignacio Torres "Estado actual de las investigaciones con IGF-I para su uso en ataxias y otras enfermedades neurodegenerativas". Instituto Cajál. CSIC. Madrid

Dr. Filip Lim "Terapia génica y progenitores neurales derivados de pacientes de ataxia". Inst. Biología Molecular Severo Ochoa. Universidad Autónoma de Madrid.

Dr. Antoni Matilla "Últimos avances en la investigación en ataxias dominantes en Europa. Formación del Centro de Investigación Biomédica en Red en enfermedades neurodegenerativas (CIBERNED) del IS Carlos III en el área de las ataxias." Inst. d´Investigació Biomédica de Bellvitge.

D. Isaac Amela Abellán “Estudio Computacional de la Interacción entre las Proteínas Clave de la Ataxia de Friedreich”.Doctorando del Laboratorio de Bioinformática del Instituto de Biotecnología y Biomedicina (IBB) de la Universidad Autónoma de Barcelona (UAB).

MESA 2: Estudios clínicos. Modera: Dr. Antoni Matilla

Dra. Benedicta Catalán y Dr. José Ramón Cano. "ataxias en nuestro medio: un estudio longitudinal en pacientes y evaluación del potencial terapéutico de proteínas neuroprotectoras Base de Datos y estudios clínicos” Servicio de Neurofisiología del Hospital Clínico de Valladolid

Dr. Javier Arpa, Dr. Francisco Domínguez, “Resultados del estudio con Idebenona y Riboflavina en pacientes con ataxia de Friedreich” “Proyecto de ensayo clínico con EPO para ataxias en el hospital” Hospital Universitario "La Paz", Madrid.

Dr. José Luís Muñoz Blanco. “Resultados de los estudios piloto efectuados en el hospital Gregorio Marañón de Madrid, con la hormona de crecimiento GH” “Proyecto de experimentación con células de glía olfatoria en enfermos de AF” Hospital Universitario Gregorio Marañón de Madrid.

Dra. Mary Kearney. “Los nuevos ensayos programados sobre ataxias de Friedreich. Últimos avances e investigaciones”. Secretaria de Euroataxia (En inglés. Traduce Dr. Antoni Matilla).

14,30 Comida.

16,00 Descanso y tiempo libre

17,30 MESA 3: Servicios informativos y sociales. Modera: Dr. Francesc Palau

Dª Mª José Planas . “Ley de dependencia. Los baremos de dependencia. Los servicios Sociales”.

D. Gian Piero Sommaruga. "FA_babelFamily Modelo de información multilingüe sobre ataxia de Friedreich” Responsable de este boletín informativo diario

Dª Isabel Campos “Enfermedades raras y los Centros de referencia. Discusión actual”.

20,30 Cena.

22,00 Fiesta y convivencia.

Domingo 17 de junio de 2007.

10,00 Desayuno

ASAMBLEA GENERAL

11,00 D. Miguel Ángel Cibrián. Dª Mafefa García de Dios. “Palabras de bienvenida y saludo” Presidente de Fedaes y Responsable relaciones.

11,20 Dª Isabel Campos. “Asamblea y actividades realizadas” Vicepresidenta de FEDAES

11,40. D. Joaquín Planas y D. Tomás Redondo. “Secretaría y cuentas” Tesorero y Secretario Fedaes.

12,00 Dª Cristina Martínez Martín. Trabajos realizados en la Sede.

12,20 Preguntas de los asistentes

13,00 Tiempo de descanso y de relaciones

13,30 Comida y despedida.

15,30 CLAUSURA

El lugar donde celebraremos las jornadas se encuentra situado en la localidad de Villagarcía de Campos en la provincia de Valladolid, en el Monasterio San Luís, regido por jesuitas.

Dado que el número de plazas adaptadas es limitado, los criterios de preferencia son:

1. Ser afiliadas a Fedaes o pertenecer a cualquiera de sus asociaciones miembros.

2. Ser enfermo de ataxia y familiar cuidador.

3. Resto de personas.

RESERVA DE PLAZA

Para la reserva de plaza será necesario rellenar el boletín de inscripción e ingresar en la cuenta de FEDAES el 50% del coste de las jornadas antes del 15 de mayo de 2007, y enviar el justificante a la sede de Fedaes en Valladolid:

Antes del 5 de junio deberá haberse ingresado el otro 50%.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17375064

1: Mol Ther. 2007 Jun;15(6):1072-8. Epub 2007 Mar 20.

Functional Recovery in a Friedreich's Ataxia Mouse Model by Frataxin Gene Transfer Using an HSV-1 Amplicon Vector.

Lim F, Palomo GM, Mauritz C, Giménez-Cassina A, Illana B, Wandosell F, Díaz-Nido J.

1Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de, Madrid, Madrid, Spain.

There is currently no effective treatment for Friedreich's ataxia (FA), the most common of the hereditary ataxias. The disease is caused by mutations in FRDA that drastically reduce expression levels of the mitochondrial protein frataxin. In FA animal models, a key difficulty is obtaining the precise levels of frataxin expression in the appropriate tissues to provoke pathology without early lethality. To develop strategies to circumvent these problems, conditional frataxin transgenic mice have been generated. We now show that frataxin expression can be eliminated in neurons from these loxP[frda] mice by infection with CRE-expressing herpes simplex virus type 1 (HSV-1) amplicon vectors. We have also achieved in vivo delivery by stereotaxic injection of these CRE-expressing vectors into the brainstem of loxP[frda] mice to generate a localized gene knockout model. These mice develop a behavioral deficit in the rotarod assay detectable after 4 weeks, and when re-injected with HSV-1 amplicon vectors expressing human frataxin complementary DNA (cDNA) exhibit behavioral recovery as early as 4 weeks after the second injection. To the best of our knowledge, this is the first proof of principle of recovery of neurological function by a therapeutic agent aimed at correcting frataxin deficiency.Molecular Therapy (2007) 15 6, 1072-1078. doi:10.1038/sj.mt.6300143.

PMID: 17375064 [PubMed - in process]

(http://health.groups.yahoo.com/group/FA_babelFAmily/message/512)

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Recupero funzionale in un modello murino di Atassia di Friedreich tramite apporto genico di fratassina utilizzando un vettore amplicon del HSV-1

Lim F, Palomo GM, Mauritz C, Giménez-Cassina A, Illana B, Wandosell F, Díaz-Nido J.

1Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de, Madrid, Madrid, Spain

Traduzione: Gian Piero Sommaruga

Per l’atassia di Friedreich (AF), l’atassia ereditaria più comune, attualmente non è disponibile alcun trattamento efficace. Questa malattia è causata da mutazioni nel gene FRDA che riducono drasticamente il livello di produzione della proteina mitocondriale fratassina. Nei modelli animali con AF la difficoltà maggiore consiste nell’ottenere gli esatti livelli di produzione di fratassina nei tessuti appropriati, per provocare la patologia, senza causare morte precoce. Per sviluppare strategie in grado di aggirare questo problema, sono stati creati dei modelli murini  transgenici per la fratassina.

Abbiamo dimostrato che l’espressione della fratassina può essere eliminata nei neuroni di questi topi loxP[frda] tramite l’infezione con vettori amplicon del virus herpes simplex di tipo 1 (HSV-1) che esprimono CRE. Siamo anche riusciti a realizzare tramite iniezione stereotassica  il trasporto in vivo  di questi vettori che esprimono CRE nel tronco cerebrale di topi loxP[frda] per generare un modello knockout con gene localizzato. Questi topi sviluppano delle difficoltà attitudinali nella prova della ruota riscontrabili a partire dalla quarta settimana e quando vengono re-iniettati con vettori amplicon HSV-1 che esprimono fratassina umana DNA complementare (Cdna) evidenziano un recupero attitudinale fin dalla quarta settimana dopo la seconda iniezione. Da quanto ci risulta, questo è il primo studio in cui è stato dimostrato un recupero delle funzioni neurologiche attraverso un agente terapeutico mirato a correggere la mancanza di fratassina.

(http://health.groups.yahoo.com/group/FA_babelFAmily/message/514)

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Recuperación  funcional en un modelo murino de Ataxia de Friedreich por aporte génico de frataxina utilizando un vector amplicón del HSV-1

Lim F, Palomo GM, Mauritz C, Giménez-Cassina A, Illana B, Wandosell F, Díaz-Nido J.

1Departamento de Biología Molecular, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, España

Traducción: MariLuz González Casas

Actualmente no existe ningún tratamiento eficaz para la ataxia de Friedreich (AF), la ataxia hereditaria más común. Esta enfermedad está causada por mutaciones en el gen FRDA que reducen drásticamente el nivel de expresión de la proteína mitocondrial frataxina. En los modelos animales con AF, la mayor dificultad consiste en obtener los niveles precisos de expresión de frataxina en los tejidos apropiados para provocar la patología sin causar muerte precoz. Para desarrollar estrategias que eviten este problema, se han creado modelos murinos transgénicos para la frataxina.

Hemos demostrado que la expresión de la frataxina puede ser eliminada de las neuronas de estos ratones  loxP[frda] por infección con vectores amplicón del virus herpes simplex de tipo 1 (HSV-1) que expresan CRE. También hemos conseguido llevar a cabo por inyección estereotáxica el transporte en vivo de estos vectores que expresan CRE en el tronco cerebral de los ratones loxP[frda] para generar un modelo knockout con gen localizado. Estos ratones desarrollan déficits funcionales en la prueba rotatoria detectables a partir de la cuarta semana, y cuando se les inyecta con vectores amplicón HSV-1 que expresan frataxina humana DNA complementaria (cDNA) evidencian recuperación funcional a partir de la cuarta semana después de la segunda inyección. De acuerdo con nuestra información, este es el primer estudio en el que se ha demostrado recuperación de las funciones neurológicas a través de un agente terapéutico dirigido a corregir la falta de frataxina.

Fonte: mailing-list dell'AFAF (Associazione Francese per l'Atassia di Friedreich)

http://fr.groups.yahoo.com/group/afaf/

Fuente: Lista de difusión de la AFAF (Asociación Francesa de Ataxia de Friedreich)

http://fr.groups.yahoo.com/group/afaf/

Ensayos en Ataxia de Friedreich

Traducción: MariLuz González Casas

Enviado por: "Juliette Dieusaert AFAF"

Fecha: Viernes, 25 de mayo 2007 15:31

Hola a todos,

sí, la investigación avanza, tanto en el plano de la investigación básica (en células, modelos murinos etc..) como en la investigación clínica (ensayos de medicamentos).

Lo he podido constatar por haber participado  de forma regular en diversos congresos y encuentros de equipos internacionales de investigación y así os lo he comunicado  desde hace varios meses: la investigación ha avanzado mucho en los últimos dos años y estamos muy contentos.

a) La actualidad en investigación fundamental  y clínica se encuentra  en el  siguiente sitio : www.afaf.asso.fr

Además se informa regularmente en la revista Espoir (ver los dos últimos números).

Las fichas sobre este tema en la carpeta “Vivre avec l'ataxie de Friedreich” están en proceso de expedición; hasta la fecha hemos enviado 560 carpetas de las cuales 500 a enfermos de ataxia; y probablemente se traduzca para EuroAtaxia.

b) Varios ensayos tendrán lugar en Francia y en otros países en 2007- 2008.

Los responsables de estos ensayos los han presentado  con ocasión del reencuentro anual de la AFAF hace 10 días.

La información que sigue a continuación se dará más detallada en junio juntamente con los contactos, una vez que las reseñas sean avaladas por sus autores podremos darles mayor difusión.

·      En principio, no debemos olvidar que un ensayo es un ensayo..: se trata de examinar una molécula que se espera que sea eficaz, pero será necesario esperar hasta el fin del ensayo para analizar los resultados; y desgraciadamente puede suceder que a veces el resultado sea decepcionante.

·        Participar en un ensayo significa poner en marcha la investigación

 
·        Se estudia la eficacia potencial de un medicamento pero también los posibles efectos secundarios.

 

·        En 2007/ 2008  tendrán lugar 3 ensayos  en Francia , a menudo en varios países de forma simultánea (ensayos multicéntricos)

      1- ensayo con Idebenona en adultos con varias dosis hasta 45 mg/kg y placebo (comprimido sin principio activo), en 5 países europeos , uno de ellos es el servicio de Alexandra Durr en la Pitié Salpêtrière; comienzo para el  verano de 2007 con duración de un año.
 

      2 - ensayo con Ferriprox en niños y adolescentes en el servicio de Arnold Munnich, Necker, y en Bélgica  para adultos con Máximo Pandolfo; su comienzo se prevé para septiembre con duración de un año.
 

      3 - ensayo con Pioglitazona para jóvenes menores de 20 años, en el servicio de Isabelle Husson - Hospital Robert Debré - a finales de año, con una duración de dos años. 

      4 - Hay otras moléculas que se están ensayando a nivel mundial (ver Espoir) y el sitio www.afaf.asso.fr

Traduction: David Miniussi 

Message de Bernhard (administrateur du forum autrichien Fataxie.net), posté le 16.05.2007 à 17:15

Dans la discussion suivante : http://www.fataxie.net/fataxie/forum/viewtopic.php?t=768  paraissait l’information (merci Luz) que le Fosfatil (Fosfolipides + Vitamine B) pourrait avoir des effets positifs sur l’AF.

La première fois que j’ai lu l’histoire du léopard sur www.ataxias.org j’avais l’impression de lire un conte, mais quand j’ai eu connaissance de manière plus approfondie de l’action engendrée sur l’organisme par les fosfolipides et les vitamines du groupe B j’ai décidé d’essayer le Fosfatil.

Je le prends depuis deux semaines et je préfère ne pas encore m’emballer, mais j’ai constaté que j’ai plus d’énergie tout au long de la journée, en tous cas plus qu’avant, et que je réussis à parler de façon plus claire.

Ce n’est pas une panacée mais ça aide!

J’ai appris que certains d’entre vous, qui participez à ce forum, prennent actuellement du Fosfatil ou des composés similaires. Il serait très intéressant de pouvoir lire vos expériences en la matière.

Message de Gixxer- 85, posté le 16.05.2007 à 19:53

Je prends actuellement moi aussi de la lécithine et un complexe de Vitamine B à forts dosages, que je fais venir des Pays bas. D’un côté, la lécithine est bien moins coûteuse que des capsules d’Essentiale et quand au contenu il est identique (Fosfolipides). Ce n’est certainement pas une panacée, mais je le prends depuis trois semaines et je note déjà des effets positifs. Je me sens bien plus en forme que d’habitude et bien plus équilibré. Dans tous les cas nous ne devons pas oublier que l’AF ne s’est pas manifestée du jour au lendemain. Je veux dire par là qu’il faut donner du temps au temps. Cependant le Fosfatil proposé par Luz me semblait sincèrement trop cher. A mon avis, 50 Euro pour les frais d’expédition, c’est trop. Quelqu’un du forum en prend-il en ce moment? De quoi s’agit-il exactement? Ce sont de simples fosfolipides, non?

Message de Togi, posté le 17.05.2007, à 09:13

Il m’est arrivé la chose suivante : j'ai montré le feuillet explicatif du Fosfatil au pharmacien et je lui ai demandé s’il pouvait préparer quelque chose de similaire. Il m’a dit que les fosfolipides sont essentiellement à base de soja et qu’ils ne sont pas chers. Ensuite il a fait une recherche sur l’ordinateur et une ordonnance.

Il s’agit d’une forme granulaire de lécithine pure de chez Bioviel, qui ne coûte que 10 Euro les 225 grammes. Une cuillère à thé correspond à cent, voire même mille fois la valeur indiquée dans le Fosfatil.

Ce produit pourrait être associé à de la vitamine B (par exemple celle de la Rathiopharm - les dosages parmi les plus forts!!! (ce détail est très important).

Il ne reste plus qu’à prendre un comprimé de vitamine B par jour et une cuillère à thé de fosfolipides.

En ce qui concerne la vit. B le dosage n’est pas aussi élevé que celui du Fosfatil, mais si on le désire on peut prendre plus de comprimés jusqu’à atteindre 75 mg par jour.

Le prix de cette combinaison est d’environ 15 Euro par mois. Dans le cas ou prend plus de comprimés de vit. B par jour (afin d’atteindre la même quantité que dans le Fosfatil), on arriverait à un montant mensuel total de 25 Euro, avec la garantie qu’il s’agit de Vit. B et de fosfolipides de bonne qualité – en la matière il est nécessaire d’être prudent.…

Au delà de toutes ces considérations, ce fut très gentil de la part de Luz de nous avoir informé de cette opportunité. Cependant, 50 Euro de frais d’expédition cela me semble sans aucun doute une demande excessive de la part de l’association des ataxies (ou de qui que soit l’intermédiaire).

Message de Gixxer, posté le 17.05.2007, à 14:13

Moi je prends celles ci, parce que ces doses massives ne sont pas en vente libre en Allemagne..

http://cgi.ebay.de/120-x-VITAMIN-B-100-mg-COMPLEX-PREMIUM-POWER_W0QQitemZ290116889206QQihZ019QQcategoryZ47874QQssPageNameZWDVWQQrdZ1QQcmdZViewItem.

mais la prochaine fois j’ai l’intention d’acheter les comprimés à effet retard qui sont sans doute meilleurs.

Message de Chris, posté le 17.05.2007, à 15:27

Salut à tous.

Jetez un oeil au lien suivant…….comprimés de Vit. B à forts dosages, d’origine naturelle. Qu’en pensez vous???

Cela semble très prometteur…..

http://www.vitalabo.at/energie/natures_plus/mega_b_s-r

Message de Chris, posté le 17.05.2007, à 15:34

Et en voici un autre sur la lécithine

http://www.vitalabo.at/energie/natures_plus/lezithin

Message de Stefan, posté le 17.05.2007, à 17:04 

Depuis environ un mois je prends de la Lécithine + de la Vitamine B, celle vendue dans toutes les pharmacies ou points de vente (de la Doppelherz, 4 Euro les 40 comprimés)

Je me sens mieux, plus fort.

Source: liste de diffusion de l’AFAF (Association Française de l'Ataxie de Friedreich)

http://fr.groups.yahoo.com/group/afaf/