Clinical pharmacokinetics and pharmacodynamics of cerliponase alfa, enzyme replacement therapy for CLN2 disease by intracerebroventricular administration

Cerliponase alfa is recombinant human TPP1 delivered by intracerebroventricular (ICV) infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. We report the PK and PD of cerliponase alfa, the first ICV enzyme replacement therapy, characterized in a Phase 1/2 study. Escalating doses (30-300 mg every two weeks, Q2W) followed by 300 mg Q2W for ≥48 weeks were administered in 24 patients aged ≥3 years. Concentrations peaked in CSF at the end of ~4-hour ICV infusion and 8 hours thereafter in plasma. Plasma exposure was 300-1000 fold lower than in CSF, with no correlation in the magnitude of Cmax or AUC between body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Inter- and intra-patient variability of AUC, respectively, were 31-49% and 24% in CSF versus 59-103% and 80% in plasma. PK variability was not explained by baseline demographics, as gender, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra-rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg ICV Q2W for CLN2 treatment

Single extreme low dose/low dose rate irradiation causes alteration in lifespan and genome instability in primary human cells

To investigate the long-term biological effect of extreme low dose ionising radiation, we irradiated normal human fibroblasts (HFLIII) with carbon ions (290 MeV u−1, 70 keV μm−1) and γ-rays at 1 mGy (total dose) once at a low dose rate (1 mGy 6–8 h−1), and observed the cell growth kinetics up to 5 months by continuous culturing. The growth of carbon-irradiated cells started to slow down considerably sooner than that of non-irradiated cells before reaching senescence. In contrast, cells irradiated with γ-rays under similar conditions did not show significant deviation from the non-irradiated cells. A DNA double strand break (DSB) marker, γ-H2AX foci, and a DSB repair marker, phosphorylated DNA-PKcs foci, increased in number when non-irradiated cells reached several passages before senescence. A single low dose/low dose rate carbon ion exposure further raised the numbers of these markers. Furthermore, the numbers of foci for these two markers were significantly reduced after the cells became fully senescent. Our results indicate that high linear energy transfer (LET) radiation (carbon ions) causes different effects than low LET radiation (γ-rays) even at very low doses and that a single low dose of heavy ion irradiation can affect the stability of the genome many generations after irradiation

Electrotransfer of Single-Stranded or Double-Stranded DNA Induces Complete Regression of Palpable B16.F10 Mouse Melanomas

Enhanced tumor delivery of plasmid DNA with electric pulses in vivo has been confirmed in many preclinical models. Intratumor electrotransfer of plasmids encoding therapeutic molecules has reached Phase II clinical trials. In multiple preclinical studies, a reduction in tumor growth, increased survival or complete tumor regression have been observed in control groups in which vector or backbone plasmid DNA electrotransfer was performed. This study explores factors that could produce this antitumor effect. The specific electrotransfer pulse protocol employed significantly potentiated the regression. Tumor regression was observed after delivery of single-stranded or double-stranded DNA with or without CpG motifs in both immunocompetent and immunodeficient mice, indicating the involvement of the innate immune system in response to DNA. In conclusion, this study demonstrated that the observed antitumor effects are not due to a single factor, but to a combination of factors

A framework for integrated environmental health impact assessment of systemic risks

Traditional methods of risk assessment have provided good service in support of policy, mainly in relation to standard setting and regulation of hazardous chemicals or practices. In recent years, however, it has become apparent that many of the risks facing society are systemic in nature – complex risks, set within wider social, economic and environmental contexts. Reflecting this, policy-making too has become more wide-ranging in scope, more collaborative and more precautionary in approach. In order to inform such policies, more integrated methods of assessment are needed. Based on work undertaken in two large EU-funded projects (INTARESE and HEIMTSA), this paper reviews the range of approaches to assessment now in used, proposes a framework for integrated environmental health impact assessment (both as a basis for bringing together and choosing between different methods of assessment, and extending these to more complex problems), and discusses some of the challenges involved in conducting integrated assessments to support policy