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2.
Nucleic Acid Ther ; 31(1): 7-20, 2021 02.
Article in English | MEDLINE | ID: mdl-33054599

ABSTRACT

The Oligonucleotide Working Group of the European Federation of Pharmaceutical Industries and Associations (EFPIA) conducted a survey of companies to understand the trends in nonclinical practices and regulatory expectations for oligonucleotide drug safety assessment. Twenty-two companies of different types, with varying oligonucleotide experience levels in the field, participated. The survey identified key regulatory challenges and areas of perceived health authority (HA) concern regarding nonclinical safety strategies for oligonucleotides, such as the choice of toxicology species, approaches to dose setting in toxicity studies, dose scaling from animals to humans, the implementation (and regulatory acceptability) of lean packages, and methods for dealing with impurities and human-specific off-targets. The perceived oligonucleotide experience of HAs and the relevance of guidance to oligonucleotide development were also assessed. The results showed a general lack of consensus on nonclinical safety assessment approaches being used for this growing class of medicines and highlight the need for continuing collaboration between sponsors and HAs to better define best practices.


Subject(s)
Drug Evaluation, Preclinical , Genetic Therapy/trends , Oligonucleotides/therapeutic use , Drug Industry , Humans , Oligonucleotides/genetics
3.
Ther Innov Regul Sci ; 50(2): 174-187, 2016 Mar.
Article in English | MEDLINE | ID: mdl-30227010

ABSTRACT

BACKGROUND: Access and use of historical control data was identified as a top stakeholder concern across organizations according to results of a survey of needs and challenges related to nonclinical data conducted by the FDA/PhUSE Nonclinical Working Group in 2011. There is a perception there may be additional ways to capitalize on historical control data to enhance studies or submissions across industry, academia, and government. During the working sessions of the FDA/PhUSE Computational Sciences Symposium in March 2012, a Historical Control subgroup of the FDA/PhUSE Nonclinical Working Group was formed to investigate how the industry might more effectively harness the vast amount of data from untreated/vehicle control animals. The subgroup includes broad representation of stakeholders with interest in nonclinical data. METHODS: This paper describes progress to date and includes results of a second survey to determine how organizations use and would like to use historical control data. RESULTS: Respondents to the survey strongly support that historical control data are useful and should be in an accessible format. Four potential project options were posed in the survey, with an overall positive response; also, several write-in options were suggested by respondents. CONCLUSIONS: Community-supported projects to increase the availability of well-annotated and scientifically curated collections of historical control data appear to be of most interest.

4.
J Biol Chem ; 285(39): 29787-96, 2010 Sep 24.
Article in English | MEDLINE | ID: mdl-20639202

ABSTRACT

The adenosine A(2A) receptor (A(2A)R) is increasingly recognized as a novel therapeutic target in Parkinson disease. In striatopallidal neurons, the G-protein α(olf) subtype is required to couple this receptor to adenylyl cyclase activation. It is now well established that the ßγ dimer also performs an active role in this signal transduction process. In principal, sixty distinct ßγ dimers could arise from combinatorial association of the five known ß and 12 γ subunit genes. However, key questions regarding which ßγ subunit combinations exist and whether they perform specific signaling roles in the context of the organism remain to be answered. To explore these questions, we used a gene targeting approach to specifically ablate the G-protein γ(7) subtype. Revealing a potentially new signaling paradigm, we show that the level of the γ(7) protein controls the hierarchial assembly of a specific G-protein α(olf)ß(2)γ(7) heterotrimer in the striatum. Providing a probable basis for the selectivity of receptor signaling, we further demonstrate that loss of this specific G-protein heterotrimer leads to reduced A(2A)R activation of adenylyl cyclase. Finally, substantiating an important role for this signaling pathway in pyschostimulant responsiveness, we show that mice lacking the G-protein γ(7) subtype exhibit an attenuated behavioral response to caffeine. Collectively, these results further support the A(2A)R G-protein α(olf)ß(2)γ(7) interface as a possible therapeutic target for Parkinson disease.


Subject(s)
Corpus Striatum/metabolism , GTP-Binding Protein gamma Subunits/metabolism , Receptor, Adenosine A2A/metabolism , Signal Transduction/physiology , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Caffeine/pharmacology , Central Nervous System Stimulants/pharmacology , GTP-Binding Protein alpha Subunits/genetics , GTP-Binding Protein alpha Subunits/metabolism , GTP-Binding Protein beta Subunits/genetics , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/genetics , Mice , Mice, Inbred BALB C , Mice, Knockout , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/therapy , Receptor, Adenosine A2A/genetics , Signal Transduction/drug effects
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