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

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

Neutrophil oxidative burst activates ATM to regulate cytokine production and apoptosis

“…51 There is currently no treatment available for AT other than palliative care. Interestingly, Chessa et al 52 found that treatment with the antiinflammatory steroid betamethasone improved neurological symptoms for AT patients, though it remains to be seen whether this effect was mediated by the immunosuppressive properties of the drug. Our work further strengthens the argument that targeting inflammation may be a promising clinical intervention for some of the symptoms of this devastating disease.…”

Ataxia telangiectasia: presentation and diagnostic delay

“…Early diagnosis is important to help ensure affected children and their families receive appropriate support with proper multidisciplinary management and the opportunity to have genetic counselling support if they would like 8. Earlier diagnosis will ensure affected children can be offered tailored support from experienced professionals, via referral to the national centre, and also an opportunity to participate in research into potential therapeutic options 9. Finally, early diagnosis will lead to avoidance of radiation-based investigations, for example, high-resolution CT (HRCT) in a radiosensitive group with an increased risk of malignancy.…”

Red blood cells: Supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems

“…The techniques by which RBC-based delivery systems would be collected and manufactured will likely depend on their application and source. As one example, the EryDex system for RBCs loaded with dexamethasone utilizes a simple 50 mL peripheral blood draw that is then loaded using a proprietary RBC loading device [202,203]. …”