Ataxia telangiectasia treated with intra-erythrocyte dexamethasone

Menotta M, Biagiotti S, Spapperi C, et al. ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T. Orphanet J Rare Dis. 2017;12(1):126. Published 2017 Jul 5. doi:10.1186/s13023-017-0669-2

Abstract

Background: Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.

Results: In the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new "ATMdexa1 variants" originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients' blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.

Conclusions: For the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.

Leuzzi V, Micheli R, D'Agnano D, et al. Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e98. Published 2015 Apr 9. doi:10.1212/NXI.0000000000000098

Abstract

Objective: Ataxia-telangiectasia (AT) is a rare, devastating neurodegenerative disease presenting with early-onset ataxia, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and proneness to cancer. In a previous phase 2 study, we showed that 6 monthly infusions of autologous erythrocytes loaded with dexamethasone (EryDex; EryDel, Urbino, Italy) were effective in improving neurologic impairment in young patients with AT. The present article reports the results of the extension of this study for an additional 24-month period.

Methods: After the end of the first trial, 4 patients continued to be treated with monthly EryDex infusions for an additional 24 months, and their clinical outcome was compared with that of 7 age-matched patients who stopped the treatment after the first 6 infusions. The protocol included serial assessment of ataxia (by International Cooperative Ataxia Rating Scale) and adaptive behavior (by Vineland Adaptive Behavior Scales) and clinical and laboratory tests revealing treatment- and steroid-dependent adverse effects, if present.

Results: Patients in the extended study experienced a continuous neurologic improvement with respect to their pretreatment status, whereas controls showed a progressive neurologic deterioration (according to the natural history of the disease) after the discontinuation of the treatment. The delivery system we adopted proved to be safe and well-tolerated, and none of the side effects usually associated with the chronic administration of corticosteroids were observed during the entire trial.

Conclusions: These promising preliminary results call for a large-scale controlled study on protracted treatment of patients with AT with dexamethasone-loaded erythrocytes.