Intra-Erythrocyte Infusion of Dexamethasone Reduces Neurological Symptoms in Ataxia Teleangiectasia Patients: Results of a Phase 2 Trial

Orphanet Journal of Rare Diseases

Mauro Magnani⁸  Damiano Abeni⁴  Stefano Tabolli⁴  Andrea Finocchi⁵  Maria Cristina Pietrogrande^1,10  Gabriella Girelli⁷  Filomena Monica Cavaliere⁷  Isabella Quinti⁷  Pierino Ferremi Leali¹  Mirella Marini¹  Elisa Fazzi⁹  Anna Molinaro³  Tullia Venturi⁶  Daniela D’Agnano⁶  Roberto Micheli⁹  Annarosa Soresina¹  Alessandro Plebani¹  Vincenzo Leuzzi⁶  Luciana Chessa² 

[1] Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute of Molecular Medicine A. Nocivelli, Spedali Civili and University of Brescia, Piazza Spedali Civili, 1 25123 Brescia, Italy;Department of Clinical and Molecular Medicine, Sapienza Università di Roma, Via di Grottarossa 1035, 00189 Roma, Italy;School in Reproductive and Developmental Science, Università di Trieste and Università di Brescia, Brescia, Piazzale Spedali Civili, 1 25123 Brescia, Italy;Istituto Dermopatico Immacolata, Via Monti Creta, 104, 00167 Roma, Italy;Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and Università di Tor Vergata, Piazza di San Onofrio 4, 00165 Roma, Italy;Department of Pediatrics and Child Neurology and Psychiatry, Sapienza Università di Roma, via dei Sabelli 108, 00185 Roma, Italy;Department of Molecular Medicine, Sapienza Università di Roma, Viale dell’Università 37, 00186 Roma, Italy;Department of Biomolecular Sciences, Università di Urbino “Carlo Bo”, Via Saffi 2, 61029 Urbino, Italy and Erydel S.p.A, Via Sasso, 61029 Urbino, Italy;Unit of Child Neurology and Psychiatry, Spedali Civili and Università di Brescia, Piazza Spedali Civili, 1 25123 Brescia, Italy;Department of Pediatrics, Università di Milano, Fondazione IRCCS Ca’ Granda, via Commenda 9, 20122 Milano, Italy

关键词: VABS;    ICARS;    Cerebellar Ataxia;    Ataxia Teleangiectasia Ataxia Treatment;    Ataxia Teleangiectasia;    Intra-Erythrocyte Dexamethasone;    Dexamethasone;   

Others  :  863315
DOI  :  10.1186/1750-1172-9-5

 received in 2013-07-12, accepted in 2013-12-27,  发布年份 2014

【 摘 要 】

Background

Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. No therapies are available for this devastating disease. Recent observational studies in few patients showed beneficial effects of short term treatment with betamethasone. To avoid the characteristic side effects of long-term administration of steroids we developed a method for encapsulation of dexamethasone sodium phosphate (DSP) into autologous erythrocytes (EryDex) allowing slow release of dexamethasone for up to one month after dosing. Aims of the study were: the assessment of the effect of EryDex in improving neurological symptoms and adaptive behaviour of AT patients; the safety and tolerability of the therapy.

Methods

Twenty two patients (F:M = 1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex. Ataxia was assessed by the International Cooperative Ataxia Rating Scale (ICARS) and the adaptive behavior by Vineland Adaptive Behavior Scales (VABS). Clinical evaluations were performed at baseline and 1, 3, and 6 months.

Results

An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n = 22; p = 0.02) as well as in patients completing the study (per protocol PP) (n = 18; p = 0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP). When compared to baseline, a significant improvement were also found in VABS (increase of the score) (p < 0.0001, ITT, RMANOVA), with statistically significant increases at 3 and 6 months (p < 0.0001). A large inter-patient variability in the incorporation of DSP into erythrocytes was observed, with an evident positive effect of higher infusion dose on ICARS score decline. Moreover a more marked improvement was found in less neurologically impaired patients. Finally, a 19 month-extension study involving a subgroup of patients suggested that Erydex treatment can possibly delay the natural progression of the disease.

EryDex was well tolerated; the most frequent side effects were common AT pathologies.

Conclusions

EryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects.

Trial registration

Current Controlled Trial2010-022315-19SpA

【 授权许可】

   
2014 Chessa et al.; licensee BioMed Central Ltd.

【 图 表 】

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