In this open-label study involving AT patients aged more than 3 years the EryDex treatment for 6 months led to a significant improvement in ICARS, the primary efficacy measure which assesses the key symptoms of the disease. Significant benefits of EryDex treatment were more relevant in the Kinetic Functions sub-scale of the ICARS and in measures assessing the patients’ adaptive behavior (VABS).
A limiting issue in all the trials focusing on AT is the lack of a dedicated rating scales to assess the complex neurologic impairment in this disease and the variable contribution of different movement disorders to the morbidity of the patients. Waiting for an ad hoc scale for A-T, which is being currently validated
, ICARS remains the most extensively used scale for children with ataxia. It is characterized by a good inter-rater reliability and it is designed for ataxic symptoms regardless of etiology
. Focusing on AT, main constraints of the scale are: the lack of a scoring subscale for dyskinetic movements (such as chorea, dystonia, athetosis, myoclonus), which are prevalent in a low percentage of AT subjects
 and the non-tailored sub items dealing with eye movement impairment and speech disorders. VABS was used in our study to provide additional information on the global functioning in term of daily living skills. In patients with a more severe neurological impairment, VABS score seemed to reflect better than ICARS score the clinical improvement detected by the clinical observation. Few studies addressed the issue of therapeutic strategies in AT patients. Nissenkorn et al.
 demonstrated that amantadine sulfate improves ataxia in AT patients with a mild impairment (ICARS 38.94 ± 10.13).
Recently, Zannolli et al.
 performed a multicenter double-blind randomized short term (30 days) trial with betamethasone vs placebo in AT patients with a moderate neurological impairment (median initial ICARS total score 44). Even though patients under betamethasone experienced a significant reduction of ICARS score, they also experienced important adverse events (increases in BMI, cholesterol, and HDL cholesterol and decrease in blood phosphorus). In contrast, in this study EryDex treatment was well tolerated during a six month trial and no variations were observed in vital signs and biochemistry. The most common TEAEs were moderate and considered ‘not related’ to the study medication, being conditions generally related to the disease.
Our results are impressive taking in consideration that most of the patients had an advanced form of the disease (score at baseline: 50.7 ± 12.8, range 42 to 68). When the patients with milder neurological involvement were considered, the improvement was more remarkable, suggesting the efficacy of treatment as function of the stage of the disease. Moreover, the clinical improvement at ICARS scores was even more relevant in patients with the most efficient dexamethasone loading in the erythrocytes. As this point is concerned, a greater proportion of females, compared to males, had mean doses of DSP of 5 mg or more. Mean value (and SD) of DSP content in the processed erythrocytes was 10.39 ± 6.28 in female, and 4.79 ± 4.68 mg/bag in male patients (n = 10 and 11 respectively) and t-test showed statistical significance of the difference between the two groups (P < 0.03). Since a higher dose was shown to correlate with a greater response on ICARS, the proportion of female patients having a clinically meaningful response (i.e. >10 ICARS point improvement on the ICARS total score at the final visit) was higher than for males. One finding that needs further exploration is the low level of DSP-erythrocyte encapsulation (almost half of the patients had mean infusion bag doses of less than 5 mg of DSP) and high level of variability in this trial, in comparison to previous studies that used EryDex as treatment device
[20–25]. This may be due to an intrinsic biochemical change in the cell membrane of the erythrocyte in AT patients, as previously reported
[26, 27]. These changes in physico-chemical properties could influence the encapsulation of DSP into AT patients’ erythrocytes and the consequent release of the active drug into the circulation. Further refinements in the procedure for loading erythrocytes with DSP are being made to ensure higher entrapment and lower intra- and inter-individual variability. No effect of age on the response to EryDex treatment was found.
This study provides support for the use of intra-erythrocyte DSP (EryDex) in the treatment of patients suffering AT, a so far untreatable disease. By continuously providing low dose levels of dexamethasone, EryDex should avoid the side effects of long-term steroid use, a great result in a population of patients which need a chronic treatment. The feasibility of a large double-blind, placebo-controlled trial should be carefully evaluated in order to confirm these preliminary findings and to assess long-term effectiveness and safety. Looking at future studies, we need to explore the efficacy of treatment in preventing or postponing the key milestones in the natural history of AT, so changing the disease course as already reported for other disorders
. From this point of view, as preliminary observation, the extended study performed in 4 subjects suggests that Erydex treatment could actually delay the natural progression of the disease.
It is worth noting that in vitro dexamethasone was shown to induce a non-canonical splicing that leads to translation of a short ATM variant retaining kinase activity. Thus, ATM may be restored by a new molecular mechanism which overcomes must of the mutations so far described in ATM gene
. Once confirmed in other studies this observation will provide the molecular basis for dexamethasone action in AT patients. Other mechanism(s) of dexamethasone that could contribute to the explanation of observed clinical improvement (i.e. dexamethasone anti-inflammatory effects) should be considered and are under investigation.