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Mono-ubiquitination of Rabphilin 3A by UBE3A serves a non-degradative function
Get PDFAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by brain-specific loss of UBE3A, an E3 ubiquitin protein ligase. A substantial number of possible ubiquitination targets of UBE3A have been identified, although evidence of being direct UBE3A substrates is often lacking. Here we identified the synaptic protein Rabphilin-3a (RPH3A), an effector of the RAB3A small GTPase involved in axonal vesicle priming and docking, as a ubiquitination target of UBE3A. We found that the UBE3A and RAB3A binding sites on RPH3A partially overlap, and that RAB3A binding to RPH3A interferes with UBE3A binding. We confirmed previous observations that RPH3A levels are critically dependent on RAB3A binding but, rather surprisingly, we found that the reduced RPH3A levels in the absence of RAB3A are not mediated by UBE3A. Indeed, while we found that RPH3A is ubiquitinated in a UBE3A-dependent manner in mouse brain, UBE3A mono-ubiquitinates RPH3A and does not facilitate RPH3A degradation. Moreover, we found that an AS-linked UBE3A missense mutation in the UBE3A region that interacts with RPH3A, abrogates the interaction with RPH3A. In conclusion, our results identify RPH3A as a novel target of UBE3A and suggest that UBE3A-dependent ubiquitination of RPH3A serves a non-degradative function
Two-year outcomes of the ARTISAN-SNM study for the treatment of urinary urgency incontinence using the Axonics rechargeable sacral neuromodulation system
No full textAims: Sacral neuromodulation (SNM) is a guideline-recommended treatment with proven therapeutic benefit for urinary urgency incontinence (UUI) patients. The Axonics® System is the first Food and Drug Administration-approved rechargeable SNM system and is designed to deliver therapy for a minimum of 15 years. The ARTISAN-SNM study was designed to evaluate UUI participants treated with the Axonics System. Two-year follow-up results are presented. Methods: One hundred and twenty-nine UUI participants underwent implantation with the Axonics System. Therapeutic response rate, participant quality of life (QoL), and satisfaction were determined using 3-day voiding diaries, ICIQ-OABqol, and satisfaction questionnaires. Participants were considered responders if they had a 50% or greater reduction in UUI episodes post-treatment. As-treated and Completers analyses are presented. Results: At 2 years, 93% of the participants (n = 121 Completers at 2 years) were therapy responders, of which 82% achieved ≥ 75% reduction in UUI episodes and 37% were dry (100% reduction). Daily UUI episodes reduced from 5.6 ± 0.3 at baseline to 1.0 ± 0.2 at 2 years. Statistically significant improvements in ICIQ-OABqol were reported. All participants were able to recharge their device and 94% of participants reported that the recharging frequency and duration were acceptable. Participant demographics nor condition severity were correlated with clinical outcomes or recharging experience. No unanticipated or serious device-related adverse events occurred. Conclusions: At 2 years, participants treated with the Axonics System demonstrated sustained safety and efficacy, high levels of satisfaction with therapy and recharging. Participant-related factors were not associated with efficacy or recharging outcomes, indicating the reported results are applicable to a diverse population
Methodological Challenges in the Economic Evaluation of a Gene Therapy for RPE65-Mediated Inherited Retinal Disease: The Value of Vision
Get PDFThe emergence of gene therapies challenge health economists to evaluate interventions that are often provided to a small patient population with a specific gene mutation in a single dose with high upfront costs and uncertain long-term benefits. The objective of this study was to illustrate the methodological challenges of evaluating gene therapies and their implications by discussing four economic evaluations of voretigene neparvovec (VN) for the treatment of RPE65-mediated inherited retinal disease. The checklist for economic evaluations of gene therapies of Drummond et al. was applied to the economic evaluations of VN performed by US Institute for Clinical and Economic Review, two country adaptations of the company model in the UK and the Netherlands, and another US publication. The main differences in methodological choices and their impact on cost-effectiveness results were assessed and further explored with sensitivity analyses using the Dutch model. To enable comparison between the economic evaluations, costs were converted to US dollars. Different methodological choices were made in the economic evaluations of VN resulting in large differences in the incremental cost-effectiveness ratio varying from US643,813 per QALY. The chosen duration of treatment effect, source of utility values, discount rate and model structure had the largest impact on the cost-effectiveness. This study underlines the findings from Drummond et al. that standard methods can be used to evaluate gene therapies. However, given uncertainty about (particularly long-term) outcomes of gene therapies, guidance is required on the acceptable extrapolation of treatment effect of gene therapies and on how to handle the uncertainty around this extrapolation in scenario and sensitivity analyses to aid health technology assessment research and align submissions of future gene therapies
UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome
Get PDFHalf a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders
The political economy of the next pandemic
Get PDFIn this working paper, I investigate what I see as the major themes for the debate that we need to have to be prepared for the next pandemic. These themes are developed against the background of a more thorough investigation in my monograph _Pandemic Economics_ (van Bergeijk 2021) about the history of pandemic research. An addendum to the book is necessary, as the pandemic and recovery constantly unfold. Humanity cannot rely on modern medicine to beat the next ‘disease X’ _and_ the world cannot afford the extortionate health and economic policy interventions during the COVID-19 pandemic again. Therefore, a major global investment project is necessary to reduce the vulnerability to and impact of pandemics. It is important to recognize that inequalities to a large extent determine pandemic vulnerability and hence, adjustment of SDGs is necessary. From the COVID-19 pandemic we learned that the international economic organizations suffered from disaster myopia and that the self-image of the advanced economies is distorted. It also has become apparent that ‘beggar-thy-neighbour’ health care was generally practiced while global health care should have been the norm. A discussion on the related issues of rationing, triage and scarcity of health care during a pandemic is urgently needed
Reorganizing the Multidisciplinary Team Meetings in a Tertiary Centre for Gastro-Intestinal Oncology Adds Value to the Internal and Regional Care Pathways. A Mixed Method Evaluation.
Get PDFIntroduction: The reorganisation of the structure of a Gastro-Intestinal Oncology
Multidisciplinary Team Meeting (GIO-MDTM) in a tertiary centre with three care
pathways is evaluated on added value.
Methods: In a mixed method investigation, process indicators such as throughput
times were analysed and stakeholders were interviewed regarding benefits and
drawbacks of the reorganisation and current MDTM functioning.
Results: For the hepatobiliary care pathway, the time to treatment plan increased, but
the time to start treatment reduced significantly. The percentage of patients treated
within the Dutch standard of 63 days increased for the three care pathways. From
the interviews, three themes emerged: added value of MDTMs, focus on planning
integrated care and awareness of possible improvements.
Discussion: The importance of evaluating interventions in oncology care pathways is
shown, including detecting unexpected drawbacks. The evaluation provides insight
into complex dynamics of the care pathways and contributes with recommendations
on functioning of an MDTM.
Conclusions: Throughput times are only partly determined by oncology care pathway
management, but have influence on the functioning of MDTMs. Process indicator
information can help to reflect on integration of care in the region, resulting in an
increase of patients treated within the Dutch standard