TY - JOUR
T1 - Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients
T2 - Results of a phase 2 trial
AU - Chessa, Luciana
AU - Leuzzi, Vincenzo
AU - Plebani, Alessandro
AU - Soresina, Annarosa
AU - Micheli, Roberto
AU - D'Agnano, Daniela
AU - Venturi, Tullia
AU - Molinaro, Anna
AU - Fazzi, Elisa
AU - Marini, Mirella
AU - Ferremi Leali, Pierino
AU - Quinti, Isabella
AU - Cavaliere, Filomena Monica
AU - Girelli, Gabriella
AU - Pietrogrande, Maria Cristina
AU - Finocchi, Andrea
AU - Tabolli, Stefano
AU - Abeni, Damiano
AU - Magnani, Mauro
PY - 2014/1/9
Y1 - 2014/1/9
N2 - 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.
AB - 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.
KW - Ataxia Teleangiectasia
KW - Ataxia Teleangiectasia Ataxia Treatment
KW - Cerebellar Ataxia
KW - Dexamethasone
KW - ICARS
KW - Intra-Erythrocyte Dexamethasone
KW - VABS
UR - http://www.scopus.com/inward/record.url?scp=84892158748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892158748&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-9-5
DO - 10.1186/1750-1172-9-5
M3 - Article
C2 - 24405665
AN - SCOPUS:84892158748
VL - 9
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
IS - 1
M1 - 5
ER -