Abstract
BackgroundAtaxia 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.MethodsTwenty 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.ResultsAn 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.ConclusionsEryDex treatment led to a significant improvement in neurological symptoms, without association with the typical steroid side effects.Trial registrationCurrent Controlled Trial 2010-022315-19SpA
Highlights
Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer
Patient population A single-arm, open-label, 6-month Phase II study was performed to assess the effect of Dexamethasone sodium phosphate encapsulated in autologous erythrocytes (EryDex) on neurological symptoms of AT patients enrolled in two centers in Italy (Department of Pediatrics and Child Neurology and Psychiatry, Sapienza University, Roma, and Department of Pediatrics, Brescia; under coordination of L.C.)
Of the 22 patients enrolled (Additional file 1: Table S1, ITT population), 16 received the six planned infusions of EryDex; 2 patients received five infusions completing the study (Per Protocol population) (Additional file 2: Table S2); 4 patients discontinued prematurely: one for withdrawal of consent, one for a protocol violation (CD4+ lymphocytes count below cut-off at baseline), and 2 for decrease in CD4+ lymphocytes count (Additional file 3: Figure S1)
Summary
Ataxia Teleangiectasia [AT] is a rare neurodegenerative disease characterized by early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent infections, radiosensitivity and proneness to cancer. AT patients with the classical phenotype present with early onset ataxia, oculocutaneous teleangiectasias, immunodeficiency, recurrent sinopulmonary infections, radiosensitivity, proneness to cancer and various neurodegenerative features. Neurologic features of AT include ataxia of the trunk and limbs, generally detected in the first years of life, progressive supranuclear ophthalmoplegia, dysarthria, swallowing incoordination, facial hypomimia and delayed peripheral neuropathy. Movement disorders such as dystonic postures and choreoathetosis could be present and in some cases prevalent. In the classical form, patients are wheel-chair dependent by the age of ten [4], and their life expectancy is around twenty-five years [5]
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