ABSTRACT
Regulatory guidelines recommend specialised safety pharmacology assessments in animals to characterise drug-induced effects on the central nervous system (CNS) prior to first-in-human trials, including the functional observational battery or Irwin test (here collectively termed neurofunctional assessments). These assessments effectively detect overtly neurotoxic drugs; however, the suitability of the in vivo assessments to readily detect more subtle drug effects on the nervous system has been questioned. A survey was formulated by an international expert working group convened by the (NC3Rs) to capture practice in CNS neurofunctional assessment tests and opinions on the perceived impact of in vivo test battery endpoints. Impact was defined as "the impact of measures alone/in combination on decision making in drug development or candidate selection when using the neurofunctional assessment". The results demonstrate that rodents are predominantly used for small molecule assessments, whereas non-rodents are frequently used to test biotherapeutics. Practice varied between respondents in terms of experimental design. Subsets of test battery endpoints were consistently considered highly impactful (e.g. convulsions, stereotypic behaviors); however, the perceived impact level of other endpoints varied depending whether drugs were designed for CNS targets. Many endpoints were considered to have no or minimal impact, whereas a subset of endpoints in CNS test batteries appears more impactful than others. A critical evaluation is required to assess whether the translational value of CNS in vivo safety pharmacology assessments could be increased by modifying or augmenting standard CNS test batteries. A revised approach to CNS safety assessment has the potential to reduce animal numbers without compromising patient safety.
Subject(s)
Drug Development/methods , Drug Evaluation, Preclinical/methods , Models, Animal , Pharmacology/methods , Animals , Central Nervous System/drug effects , Drug Development/legislation & jurisprudence , Drug Development/statistics & numerical data , Drug Evaluation, Preclinical/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/prevention & control , Humans , Pharmacology/legislation & jurisprudence , Research Design/legislation & jurisprudence , Research Design/statistics & numerical data , Surveys and QuestionnairesSubject(s)
Codon, Nonsense , Drug Approval , Dystrophin/genetics , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/genetics , Oxadiazoles/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Clinical Trials, Phase II as Topic , Humans , Male , Randomized Controlled Trials as Topic , Treatment Outcome , Young AdultABSTRACT
Dorsal horn neurons in the spinal cord integrate and relay sensory information. Here, we show that the expression of the homeobox gene Lbx1 distinguishes two major neuronal classes generated in the dorsal spinal cord. The Lbx1(-) (class A) and Lbx1(+) (class B) neurons differ in their dependence on roof plate BMP signals for specification and settle in the deep and superficial dorsal horn, respectively. Lbx1 misexpression blocks the differentiation of class A neurons. Conversely, in Lbx1 mutant mice, class B neurons assume the identity of class A neurons. As a consequence, the morphology and neuronal circuitry of the dorsal horn are aberrant. We conclude that Lbx1 distinguishes two major neuronal classes in the dorsal spinal cord and is an important determinant of their distinct differentiation programs.
