UniQure (Netherlands)

Electroencephalogram (EEG) has been the gold standard for measuring epileptic activity in rodent models of epilepsy. Manual scoring of seizures in EEG recordings lasting from days to months is laborious and prone to human error. The existing literature on automatic seizure detection in rodent models of epilepsy is limited, and the electrographic characteristics of induced epilepsy significantly differ from those of other epilepsy types. This study employed a Light Gradient Boosting Machine (LightGBM), with the dataset carefully partitioned into separate training and testing sets to ensure no data overlap. The model was trained using five-fold cross-validation to enhance robustness and generalisability. The training, validation, and independent test sets comprised 29,722 h of EEG recordings from 102 mice with pilocarpine-induced temporal lobe epilepsy. Following feature selection, model training, and post-processing, the lightGBM-based model exhibited a sensitivity of 80%, a specificity of 99%, and an F1-score of 0.71 on the independent test set. Multiple pairwise and non-parametric statistical tests indicated that envelope, skewness, and kurtosis, identified as the three most significant features in the feature importance ranking, exhibit statistically significant differences in their distributions (p-value < 0.05). The statistical analysis revealed significant differences across the three features and between seizure and non-seizure events for each feature, highlighting their relevance for discriminating epileptic activity. This study highlights the potential to support the automation of seizure event detection in preclinical rodent models of epilepsy.

Pre-existing neutralizing antibodies (NAb) to adeno-associated virus (AAV) may diminish the efficacy of AAV-based therapies depending on the titer. To support gene therapy studies in pigs, the seroprevalence of NAb to AAV1, 2, 5, 6, 8, and 9 serotypes were assessed in the sera of 3 different strains of pigs consisting of 60 Norsvin Topigs-20 strain, 22 Gottingen minipigs, and 40 Yucatan minipigs. Cell-based NAb assays were developed for various AAV serotypes. The sera were tested for NAb in a Lec-2 cell line for AAV9 vector and in a COS-7 cell line for the other AAV serotypes. In the 60 Topigs-20 strain 2 to 4 years of age, 100% were positive for AAV2 NAb, 45% positive for AAV6 NAb, and ∼20% positive for each of AAV1, 5, 8, and 9 NAb. These data showed that ∼80% of Norsvin Topigs-20 pigs evaluated were seronegative for pre-existing NAb to the AAV1, 5, 8, and 9 serotypes, respectively. In 22 Gottingen minipigs at 5-6 months of age, serum AAV serotype-specific NAb coexisted with that of various other AAV serotypes at 32% to 46% between two serotypes. These results suggested that coexisting NAb resulted either from multiple AAV serotype coinfection or from one (or more) serotypes that can crossreact with other AAV serotypes in some minipigs. Among the 40 Yucatan minipigs, 20 of the minipigs were <3 months old and were all negative for NAb against AAV5, 8, and 9, and only one of these 20 pigs was positive to AAV1 and 6. We further determined the titers in those positive pigs and found most Gottingen minipigs had low titer at 1:20, whereas some of Topigs-20 pigs had titers between 1:80 and 1:320, and some of Yucatan pigs had titers between 1:160 and 1:640. These results suggested that the majority of the pigs in the three strains would be amenable to gene therapy study using AAV1, AAV5, AAV8, and AAV9 and that prescreening on circulating AAV antibodies could be helpful before inclusion of pigs into studies.

Objective Gene therapy aims to provide long-term therapeutic benefit from a single administration. AMT-060, an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter, is being evaluated in 10 adults with severe/moderate-severe hemophilia B. over 5 years. Aim: To describe efficacy and safety outcomes from an analysis up to 5-years post-AMT-060 (Phase 1/2 study, NCT02396342).

Gene therapy is an emerging and powerful therapeutic tool to deliver functional genetic material to cells in order to correct a defective gene. During the past decades, several studies have demonstrated the potential of AAV-based gene therapies for the treatment of neurodegenerative diseases. While some clinical studies have failed to demonstrate therapeutic efficacy, the use of AAV as a delivery tool has demonstrated to be safe. Here, we discuss the past, current and future perspectives of gene therapies for neurodegenerative diseases. We also discuss the current advances on the newly emerging RNAi-based gene therapies which has been widely studied in preclinical model and recently also made it to the clinic.