open trail of γifn for friedreich ataxia

Conditions: Friedreich Ataxia

Summary: the investigator proposes an open label pilot study to investigate the safety and efficacy of gamma interferon (γifn) in patients with friedreich's ataxia (frda). yifn, an approved drug for treatment of granulomatous disease, has been shown to promote frataxin expression in frda models in vitro and in vivo as well as in pilot human studies. safety will monitored by clinical surveillance and biohumoral periodic assessment. efficacy will be assessed by a combination of advanced neuroimaging techniques and established clinical indicators. the investigators intend to recruit over a 6 months period 12 subject with molecularly established frda. the protocol builds on a recently concluded observational study which established the pattern of clinical and neuroimaging abnormalities characterizing a cohort of patients with fa. the data already acquired through such study will constitute the t-6/-12 point, and together with t0 assessment, carried out at study entrance, will provide for each patient the exact appreciation of disease actual progression over a year time. recruited patients will receive for 6 months yifn at a final dose of 200 ug/three times a week. patients will be evaluated clinically after 3 and 6 months (t3 and t6) of treatment and 6 months after treatment end (t+6) and by neuroimaging at t6 and t+6. the neuroimaging protocol, based on 3 tesla scanner, consists in functional mri, tractography. the clinical protocol consists on specific ataxia scales administration. regular monitoring with for eventual adverse events will be provided. frataxin levels in the peripheral blood mononuclear cells will also be evaluated at t0, t3, t6, t+6. furthermore, the thickness of the cardiac ventricle and retinal nerve fibre layer (rnfl) thickness with optical coherence tomography (oct) will be performed at t0, t6, t + 6.

friedreich ataxia (frda) is a devastating neurodegenerative disease that affects children and young adults. patients become progressively unable to coordinate movements and walking until severe disability ensues. most patients develop dilated cardiomyopathy and congestive heart failure. the disease is non remissive and significantly shortens lifespan expectancy. frda is a genetic disease inherited in an autosomal recessive fashion. frda patients display abnormal gaa triplet expansions within the first intron of the frataxin gene that prevent proper gene expression. the levels of frataxin, a mitochondrial protein involved in iron metabolism and energy production, are insufficient and cells undergo prolonged stress and premature death. mostly affected by frataxin deficiency are peripheral neurons of the dorsal root ganglia (drg) and neurons of the cerebellar nucleus dentatus. frda affects 1 in 50,000 individuals in western countries and has no approved therapy. it has recently been shown that interferon gamma (γifn), a natural regulator of the immune response and iron metabolism, stimulates frataxin gene transcription and promotes frataxin accumulation in cells, including frataxin-defective cells derived from frda patients. moreover, prolonged treatment of yg8r mice, an animal model for frda, with γifn results in accumulation of frataxin in drg neurons and significantly prevents the deterioration of the sensorimotor performances of the mice over time. since γifn is also a drug available on the market as a recombinant protein (γifn - 1b, td imukin® and actimmune®), and already approved for two pediatric indications (malignant osteopetrosis and chronic granuloumatous disease), it could represent a quickly accessible therapeutic option for frda patients. a major obstacle to efficiently establish efficacy of treatment in frda is the lack of reliable and sensitive biomarkers. clinical indicators (disease specific scales, timed performance tests) are prone to inter-rater variability and, above all, while valid and sensitive to long term changes, they are very inefficient in capturing changes in the short time interval (months) typically used in randomized clinical trials (rcts). the advanced neuroimaging techniques such as voxel-based morphometry (vbm), susceptibility weighted imaging (swi), diffusion tensor imaging (dti) and functional magnetic resonance imaging (fmri) could offer objective indicators of the disease progression that could serve as paraclinical end point in therapeutic trials. surrogate end-points based on neuroimaging indicators have been extensively used in other neurological diseases such as multiple sclerosis, and their introduction speeded up significantly the recognition of effective treatments and their longitudinal evaluation. in the last years, in vivo mri studies have provided information relative to the damage of cerebellar, cerebral and spinal cord areas involved in frda and other genetically determined ataxias, which could be useful to monitor disease progression. with the advent of the vbm, it is possible to quantify the degree of atrophy, to monitor it in time and to identify various pattern typical of a specific form of ataxia. various studies have evidenced a significant correlation between the degree of the cerebellar atrophy, the severity of the clinical picture and also the duration of the disease . a pilot study conducted in a cohort of 9 frda affected adolescents who underwent a 6 month treatment with deferiprone, demonstrated a significant reduction in the mean r2\* signal in the cerebellar dentate nuclei, an iron tissue store index. modifications of the fmri pattern in response to specific tasks involving both the motor and the planning ability have also been demonstrated in frda patients, and fmri based protocols could offer an adjunctive indicator of disease progression or of therapy induced modification. aims and purpose of the proposed investigation: * test safety of γifn treatment given for 6 months at final dose of 200 mcg three times weekly in frda patients. * test the effect of γifn treatment on disease specifc clinical scale (sara) * test the effect of such treatment on a set of secondary imaging, laboratory and clinical end-points: * fmri changes in frda patients performing the finger tapping protocol * dti parameters * thickness of ventricular wall as measured by ecocardiogram (ecocg) * thickness of rnfl as measured by oct * frataxin levels in cell lysates prepared from peripheral blood mononuclear cells (pbmc) * changes in quality of life and disability impact measure. what previous work is this project based on? evidence for the possible efficacy of recombinant γifn in frda has been gathered both in the animal model for the disease and in frda patients. in frda patients, a recently completed phase ii trial reported significant improvement on the fars evaluation after 3 months treatment on a 100 mcg, 3 times/weekly regimen. moreover, another recently completed phase ii study suggests that the dosing of 200 mcg is reasonably well tolerated in frda patients. an articulated mri protocol for frda patients aged 12-50 which included dti, vbm, and fmri following a selective motor paradigm has been tested, validated and implemented in the investigators institute. by this protocol the investigators evaluated 22 frda patients and 15 age and sex matched healthy controls, and found significant differences in dti parameters (fa \& md) in the cerebellar white matter, long sensory and motor tracts, major commissural tracts, and in bold signal intensity and distribution of bold signal during performance of a finger tapping test. these latter disease specific changes were most evident in the ipsilateral cerebellar cortex. the observed changes correlated with the degree of neurological and functional impairment as measured with validated scales. these preliminary results indicate that dti and fmri changes may function as efficient surrogate end-points in rct for frda patients. design open label pilot study. primary safety end point: safety of γifn 6 month treatment at doses of 200 mcg 3 times a week primary efficacy end point: sara score changes during the treatment period compared to those registered during the pre-treatment period and the post-treatment follow-up period secondary end-points: o changes in: bold signal obtained during the selective motor task (finger tapping) * dti parameters (fa, md) in the cerebellar white matter, the long and the commissural tracts * ventricular wall thickness (eco cg) • rnfl thickness (oct) * frataxin content in pbmc * changes in qol measure (sf-36) * changes in disability measure (who-das 2.0) subjects inclusion criteria: * molecularly defined frda, * willingness to participate in the study and signing of the informed consent form. in order to control for the ongoing deterioration associated with the disease, the investigators will recruit only those patients who had been already studied with the mri protocol and the functional scales indicated below 12 months before the beginning of the present study. exclusion criteria: * presence of any contraindication for mri study, * presence of clinically significant heart, liver or kidney disease or other medically unstable conditions. * known sensitivity to γifn. * previous exposure to recombinant hematopoietin. * ongoing use of desferiprone or other specific frda treatmenent * pregnancy or lactation study drug γifn (imukin 100 mcg/vial) treatment will be: 1. st two weeks: 100 mcg/three times a week from the 3rd week: 200 mcg three times a week for the following 22 weeks imaging protocol the mri examination will be administered at 4 t points: - t-12 to -6: for this point the data already stored along in the last year from the published invesitgators' mri study on 18 subjects will be used - t0: at time of recruitment - t6: after 6 months of treatment - t+6: 6 months after treatment termination the protocol will be acquired on a 3 t scanner equipped with a 32-channel head coil and will include morphological, structural (dti) and functional (fmri) sequences. a 3d t1-weighted tfe sequence (tr/te=8.2/3.7, voxel size= 1x1x1 mm, 150 slices) will be acquired in order to obtain morphological data suitable for volumetric analysis for voxel-based morphometry. the dti data will be acquired by means of a t2-weighted epi sequence (voxel size =2.5x2.5x2.5 mm) along 32 non-collinear directions, with multiple b-values (0, 300, 1100 sec/mm2) and will be evaluated off-line with the tortoise dedicated software. functional data will be acquired by means of a t2-weighted epi sequence (tr/te=2000/20, thickness=2.5mm, 40 slices) covering the whole brain and cerebellum. functional images will be acquired during a task that implies manual coordination and precision, in order to test possible effect of the treatment over the functional organization of motor networks. laboratory protocol eco cg study will be performed at t0, t6, t+6 with established protocol. frataxin levels monitoring will be performed at t0, t3 (after 3 months) and t6 (after 6 months). clinical measures and safety monitoring a trained neurologist will visit each patient at t0, t3, t6 and t+6 and report all vital signs and register other objective findings including adverse event (ae). a detailed checklist with all the known ae reported with γifn treatment will be presented to each participant at t0, t3, t6. the following blood test will be performed at t0, t3, t6 : -cell blood count, erythrocyte sedimentation rate, ca2+, cl-, na+, mg2+, k+, albumin, globulins, glucose, blood urea nitrogen, uric acid, creatinine, aspartate transaminase, alanine transaminase, iron, ferritin, transferrin statistical analysis for the mri protocol, each dataset will be processed with a dedicated pipeline and appropriate software. the t1 volumes will be processed following the standard fmrib software library (fsl) pipeline and performing vbm. as first step a study specific template of gray matter, using the routine "buildtemplateparallel" of advanced normalization tools (ants), that performs an iterative template construction with elastic transformations will be created. the dti data will be corrected for eddy currents and motion artefacts and then the diffusion tensor will be computed using the non-linear mono-exponential diffusion model, obtaining maps of "fractional anisotropy" (fa), "mean diffusivity" (md), "radial diffusivity" (rd) and "axial diffusivity" (ad). to quantify the statistical differences over time, the diffusion data of all subjects will be moved to a common space through rigid, affine and diffeomorphic registrations based on the diffusion tensor itself. using the transformations computed on the tensors, 3 different tests will be performed: - tract based spatial statistics (tbss); - voxel-wise statistical analysis based on permutations; - statistical analysis of regions of interest (roi) with generalized linear models (glm). the fmri data will be processed using statistical parametric mapping 8 (spm8). a first-level fixed effect analysis will be performed on each subject using global linear model and motion parameters as confounds. for the group-level analysis a random effect analysis with contrasts obtained in the single subject step analysis will be performed. a two sample t-test will finally be computed to check differences in activations over time. all time-dependent data (including roi-wise neuroimaging results) will be analyzed using multivariate linear mixed models, including timepoints as a repeated within-subject factor and included sex, age at onset, disease duration, years of education and number of gaa1 repeats within the smaller fxn allele as covariates of no interest. n case of a statistically significant (p\<0.05) overall effect of time, pairwise comparisons between timepoints will be performed and corrected for multiple comparisons across pairs of timepoints. correlation analysis will also be 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Eligibility criteria:
inclusion criteria: * molecularly defined frda, * willingness to participate in the study and signing of the informed consent form. * in order to control for the ongoing deterioration associated with the disease, the investigator will recruit only those patients who had been already studied with the mri protocol and the functional scales indicated below approxymately 12 months before the beginning of the present study. exclusion criteria: * presence of any contraindication for mri study, * presence of clinically significant heart, liver or kidney disease or other medically unstable conditions. * known sensitivity to γifn. * previous exposure to recombinant hematopoietin. * ongoing use of desferiprone or other specific frda treatments. * pregnancy or lactation