Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa.

BACKGROUND: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. RESULTS: We evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment). CONCLUSION: We show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.

E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy.

The distinction of self from non-self is crucial to prevent autoreactivity and ensure protection from infectious agents and tumors. Maintaining the balance between immunity and tolerance of immune cells is strongly controlled by several sophisticated regulatory mechanisms of the immune system. Among these, the E3 ligase ubiquitin Casitas B cell lymphoma-b (Cbl-b) is a newly identified component in the ubiquitin-dependent protein degradation system, which is thought to be an important negative regulator of immune cells. An update on the current knowledge and new concepts of the relevant immune homeostasis program co-ordinated by Cbl-b in different cell populations could pave the way for future immunomodulatory therapies of various diseases, such as autoimmune and allergic diseases, infections, cancers and other immunopathological conditions. In the present review, the latest findings are comprehensively summarized on the molecular structural basis of Cbl-b and the suppressive signaling mechanisms of Cbl-b in physiological and pathological immune responses, as well as its emerging potential therapeutic implications for immunotherapy in animal models and human diseases.

The effect of activated charcoal on phenytoin pharmacokinetics.

STUDY OBJECTIVES: To examine the effect of administration of oral activated charcoal with or without sorbitol on the elimination of phenytoin. SETTING: Emergency department of a rural teaching institution. TYPE OF PARTICIPANTS: Eight normal volunteers. INTERVENTIONS: Subjects received 15 mg/kg phenytoin as an IV infusion. During the first phase of the study, oral activated charcoal was administered to a total dose of 140 g over a ten-hour period. During the second phase of the study, phenytoin alone was administered. MEASUREMENTS AND MAIN RESULTS: Administration of activated charcoal resulted in a significant decrease in the area under the curve 0-inf (p = .008) and in total body clearance (P = .008). No difference in the effect on phenytoin pharmacokinetic parameters was noted when the charcoal was administered with or without sorbitol, but fewer gastrointestinal adverse effects were noted without sorbitol treatment. CONCLUSION: Oral activated charcoal was shown to affect phenytoin pharmacokinetic parameters. Further pharmacokinetic/pharmacodynamic studies are warranted to determine if activated charcoal results in a faster recovery from phenytoin toxicity.