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

Luciana Chessa1, Vincenzo Leuzzi2*, Alessandro Plebani3, Annarosa Soresina3, Roberto Micheli4, Daniela D’Agnano2, Tullia Venturi2, Anna Molinaro5, Elisa Fazzi4, Mirella Marini3, Pierino Ferremi Leali3, Isabella Quinti6, Filomena Monica Cavaliere6, Gabriella Girelli6, Maria Cristina Pietrogrande7, Andrea Finocchi8, Stefano Tabolli9, Damiano Abeni9 and Mauro Magnani10

Author Affiliations

1 Department of Clinical and Molecular Medicine, Sapienza Università di Roma, Via di Grottarossa 1035, 00189 Roma, Italy

2 Department of Pediatrics and Child Neurology and Psychiatry, Sapienza Università di Roma, via dei Sabelli 108, 00185 Roma, Italy

3 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

4 Unit of Child Neurology and Psychiatry, Spedali Civili and Università di Brescia, Piazza Spedali Civili, 1 25123 Brescia, Italy

5 School in Reproductive and Developmental Science, Università di Trieste and Università di Brescia, Brescia, Piazzale Spedali Civili, 1 25123 Brescia, Italy

6 Department of Molecular Medicine, Sapienza Università di Roma, Viale dell’Università 37, 00186 Roma, Italy

7 Department of Pediatrics, Università di Milano, Fondazione IRCCS Ca’ Granda, via Commenda 9, 20122 Milano, Italy

8 Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and Università di Tor Vergata, Piazza di San Onofrio 4, 00165 Roma, Italy

9 Istituto Dermopatico Immacolata, Via Monti Creta, 104, 00167 Roma, Italy

10 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

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Orphanet Journal of Rare Diseases 2014, 9:5  doi:10.1186/1750-1172-9-5

Published: 9 January 2014

Abstract

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 Trial 2010-022315-19SpA

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