The basics of preclinical drug development for neurodegenerative disease indications

Steinmetz, Karen L.; Spack, Edward G.

doi:10.1186/1471-2377-9-s1-s2

Cited by 97 publications

(71 citation statements)

References 3 publications

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“…Even in fields with an established translational tradition, such as oncology, it can take ,10 years to complete translation. The process involves preclinical basic studies to determine efficacy, safety, and pharmacokinetics in mammals, usually in at least two species and following the good laboratory practice (GLP) conditions specified by regulatory agencies (Steinmetz and Spack 2009). Clinical outcome measures need to be selected that have been validated clinically, are reproducible, can be measured in a short time frame, are as noninvasive as possible, are accepted by regulatory agencies, and for which there are acceptable animal models.…”

Section: Initial Clinical Trials Scenariosmentioning

confidence: 99%

Translating the Science of Aging into Therapeutic Interventions

Kirkland

2016

Cold Spring Harb Perspect Med

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Section: Initial Clinical Trials Scenariosmentioning

confidence: 99%

Translating the Science of Aging into Therapeutic Interventions

Kirkland

2016

Cold Spring Harb Perspect Med

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“…Nature-derived approved and clinical-trial drugs and their species origins were obtained from published reviews (1,2,19) and our own literature search (SI Appendix, Table S8). Preclinical drugs are drug candidates that have entered preclinical studies such as safety, pharmacokinetics/absorption, distribution, metabolism, and excretion, active pharmaceutical ingredient preparation, and formulation (33). Following the seminal works on nature-derived drugs (1, 2), we included in our analysis biologics, natural products and their semisynthetic derivatives, mimics, and peptidomimetics.…”

mentioning

confidence: 99%

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

Zhu

Chu

Lin

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

231

190

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Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.

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“…For small molecules and proteins, these activities are clearly defi ned by regulatory authorities, and primarily focus on demonstrating the physical characteristics, pharmacology, and safety of the drug candidate (Steinmetz and Spack 2009 ). Cellular therapeutics also require defi nition of composition and safety, but the complexity of cells and the challenges of defi ning potency add to the set of preclinical development issues.…”

Section: Overviewmentioning

confidence: 99%

Guidelines for Preclinical Development

Spack

2016

Regenerative Medicine - From Protocol to Patient

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Preclinical development encompasses the set of activities required to initiate testing for safety and effi cacy in humans. These requirements are defi ned by national and international regulations, and are generally focused on defi nition of drug composition and safety as well as scientifi c rationale and establishing a proposed dose regimen. The preclinical regulatory requirements for cell therapies broadly parallel those for small molecules and proteins, but the complexity of cells can bring additional challenges to the defi nition of potency, composition, immunogenicity, and toxicity. As a consequence of their pluripotent origins, stem cell therapies require additional preclinical considerations related to potential tumorigenicity and genetic/epigenetic stability. The fi rst FDA approved stem cell therapy study initiated clinical trial in 2010. Thus, the fi eld is young and there are few completed studies to provide precedents for planned preclinical development of novel stem cell approaches. Rather, the fi eld must draw practical lessons from other somatic cell therapies. The evolution and harmonization of regulatory guidances for stem cells must also contend with a growing number of unregulated sites around the world that offer unproven stem cell treatments. It takes time for any new technology to identify safety and effi cacy barriers to clinical application, and to develop strategies to overcome them. As current research and clinical experience guide the next generation of stem cell therapies in preclinical development, the establishment of validated assays based on cells differentiated from human stem cells may revolutionize the preclinical safety testing for all classes of drugs.

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The basics of preclinical drug development for neurodegenerative disease indications

Cited by 97 publications

References 3 publications

Translating the Science of Aging into Therapeutic Interventions

Translating the Science of Aging into Therapeutic Interventions

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

Guidelines for Preclinical Development

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