A Randomized First-in-Human Study With UB-312, a UBITh® α-Synuclein Peptide Vaccine.

BACKGROUND: α-Synuclein (αSyn) is believed to play a central role in Parkinson's disease (PD) neuropathology and is considered a target for disease modification. UB-312 is a synthetic αSyn peptide conjugated to a T helper peptide and is expected to induce antibodies specifically against oligomeric and fibrillar αSyn, making UB-312 a potential immunotherapeutic for synucleopathies. OBJECTIVE: To investigate the safety, tolerability, and immunogenicity of UB-312 vaccination in healthy participants and to determine a safe and immunologically optimal dose for the first-in-patient study. METHODS: Fifty eligible healthy participants were enrolled in a 44-week, randomized, placebo-controlled, double-blind study. Participants in seven cohorts were randomized to three intramuscular UB-312 or placebo injections at weeks 1, 5, and 13 (doses ranging between 40 and 2000 µg). Safety and tolerability were assessed by adverse events, clinical laboratory, vital signs, electrocardiograms, and neurological and physical examinations. Immunogenicity was assessed by measuring serum and cerebrospinal fluid (CSF) anti-αSyn antibody concentrations. RESULTS: Twenty-three participants received all three vaccinations of UB-312. Most adverse events were mild, transient, and self-resolving. Common treatment-emergent adverse events included headache, nasopharyngitis, vaccination-site pain, lumbar puncture-site pain, and fatigue. UB-312 induced dose- and time-dependent antibody production. Antibodies were detectable in serum and CSF of all participants receiving the 300/300/300 µg UB-312 dose regimen. The average CSF/serum ratio was 0.2%. CONCLUSIONS: UB-312 was generally safe, well tolerated, and induced anti-αSyn antibodies in serum and CSF of healthy participants. The 100 and 300 µg doses are selected for further evaluation in participants with PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Antisense oligonucleotide therapeutics in neurodegenerative diseases: the case of polyglutamine disorders.

Polyglutamine (polyQ) disorders are a group of nine neurodegenerative diseases that share a common genetic cause, which is an expansion of CAG repeats in the coding region of the causative genes that are otherwise unrelated. The trinucleotide expansion encodes for an expanded polyQ tract in the respective proteins, resulting in toxic gain-of-function and eventually in neurodegeneration. Currently, no disease-modifying therapies are available for this group of disorders. Nevertheless, given their monogenic nature, polyQ disorders are ideal candidates for therapies that target specifically the gene transcripts. Antisense oligonucleotides (ASOs) have been under intense investigation over recent years as gene silencing tools. ASOs are small synthetic single-stranded chains of nucleic acids that target specific RNA transcripts through several mechanisms. ASOs can reduce the levels of mutant proteins by breaking down the targeted transcript, inhibit mRNA translation or alter the maturation of the pre-mRNA via splicing correction. Over the years, chemical optimization of ASO molecules has allowed significant improvement of their pharmacological properties, which has in turn made this class of therapeutics a very promising strategy to treat a variety of neurodegenerative diseases. Indeed, preclinical and clinical strategies have been developed in recent years for some polyQ disorders using ASO therapeutics. The success of ASOs in several animal models, as well as encouraging results in the clinic for Huntington's disease, points towards a promising future regarding the application of ASO-based therapies for polyQ disorders in humans, offering new opportunities to address unmet medical needs for this class of disorders. This review aims to present a brief overview of key chemical modifications, mechanisms of action and routes of administration that have been described for ASO-based therapies. Moreover, it presents a review of the most recent and relevant preclinical and clinical trials that have tested ASO therapeutics in polyQ disorders.

Prefrontal cortex lesions and scopolamine impair attention performance of C57BL/6 mice in a novel 2-choice visual discrimination task.

Sustained attention is defined as the ability or capacity to remain focused on the occurrence of rare events over long periods of time. We describe here the development of a novel, operant-based attention task that can be learned by mice in 8-10 days. Mice were trained on a 2-choice visual discrimination task in an operant chamber, wherein the correct response on any given trial was a lever-press cued by a stimulus light. Upon reaching a criterion of greater than 80% correct responses, all subjects were tested in a mixed-trial attention paradigm combining four different stimulus durations within a single session (0.5, 1, 2, or 10 s). During attention testing, the percentage of correct responses decreased as a function of stimulus duration, indicating a performance decrement which parallels increasing attentional demand within the task. Pretreatment with the muscarinic-receptor antagonist scopolamine yielded a reliable, dose-dependent performance deficit whereas nicotine treatment improved the percentage of correct responses during trials with the greatest attentional demand. Moreover, medial prefrontal cortex lesions impaired attention performance without affecting acquisition or retention of the discrimination rule. These results underscore the utility of this task as a novel means of assessing attentional processes in mice in a relatively high-throughput manner.