Preclinical pharmacology of glucosylceramide synthase inhibitor venglustat in a GBA-related synucleinopathy model

Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson’s disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.

Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.

The impact of using virtual patients in preclinical pharmacology teaching

To reduce medication errors, medical educators must nurture the early development of rational and safe prescribing. Teaching pharmacology is challenging because it requires knowledge integration across disciplines, including physiology and pathology. Traditionally, pharmacology has been taught using lecture-based learning, which conveys consistent information but may promote passive learning. Virtual patients (VPs) have been used more recently to promote active learning, mainly in clinical years. Conversely, the use of VPs in preclinical disciplines, including pharmacology, is not well described. The objective was to investigate the potential benefits of combining traditional teaching with VPs in preclinical pharmacology teaching. All year 3 medical students (2 cohorts), enrolled in the Systematic Pharmacology I course (lectures: 3 h weekly; tutorial: 1 h weekly), were invited to participate in this naturalistic, prospective study. During tutorials, students were taught using case-based discussion and single-best-answer questions (control) in four tutorials and VPs (experimental) in the remaining six tutorials. The impact of VPs was assessed by 1) performance in written examinations, and 2) student satisfaction/perceptions, using a validated, modified questionnaire. Examination performance related to teaching in VP-based tutorials was significantly improved, compared with traditional tutorials. The level of difficulty of control and experimental assessment items was comparable, as determined by the Angoff method. Facilitation of learning was higher in VP tutorials, while a no-harm effect was noted on knowledge acquisition/maintenance, authenticity of learning, and disadvantages of learning. VPs may be effectively integrated in preclinical pharmacology teaching, with benefits on pharmacological knowledge and facilitation of learning.

An Eye on the Dog as the Scientist’s Best Friend for Translational Research in Ophthalmology: Focus on the Ocular Surface

Preclinical animal studies provide valuable opportunities to better understand human diseases and contribute to major advances in medicine. This review provides a comprehensive overview of ocular parameters in humans and selected animals, with a focus on the ocular surface, detailing species differences in ocular surface anatomy, physiology, tear film dynamics and tear film composition. We describe major pitfalls that tremendously limit the translational potential of traditional laboratory animals (ie., rabbits, mice and rats) in ophthalmic research, and highlight the benefits of integrating companion dogs with clinical analogues to human diseases into preclinical pharmacology studies. This One Health approach can help accelerate and improve the framework in which ophthalmic research is translated to the human clinic. Studies can be conducted in canine subjects with naturally occurring or non-invasively induced ocular surface disorders (eg., dry eye disease, conjunctivitis), reviewed herein, and tear fluid can be easily retrieved from canine eyes for various bioanalytical purposes. In this review, we discuss common tear collection methods, including capillary tubes and Schirmer tear strips, and provide guidelines for tear sampling and extraction to improve the reliability of analyte quantification (drugs, proteins, others).