Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Colman, Karyn

doi:10.1177/0192623316672743

Cited by 19 publications

(29 citation statements)

References 45 publications

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“…In particular, cynomolgus monkeys of Mauritian origin are considered to be genetically very different from those of East Asian origin. They also show little interindividual genetic variance compared to East Asian macaques; this is attributed to a small founder representation and subsequent rapid population expansion on an isolated island because Mauritian macaques are thought to have been brought to Mauritius as sailor companions from Java and Sumatra in the 17th or 18th century (Colman 2017; Kanthaswamy et al 2008, 2013). In addition to genetics, Mauritian cynomolgus monkeys exhibit some physiological differences and a different spectrum of background changes compared to cynomolgus monkeys of Cambodian or Asian hybrid origin (Kozlosky et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Findings in the Eyes of Cynomolgus Monkeys (Macaca fascicularis) of Mauritian Origin

Woicke

Hailé²,

Mysore

et al. 2018

Toxicol Pathol

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Spontaneous findings noted in the eyes of Mauritian cynomolgus monkeys are described and descriptions are supplemented with illustrations. Findings observed after extensive histopathologic examinations (20 to 44 sections per eye) from 20 control, 17 treatment-naive stock monkeys, and 2 findings noted in drug-treated monkeys that were considered to be spontaneous are included. Also included are findings from 361 control monkeys of routine toxicity studies performed at our laboratories, for most of which a standard histopathological examination of 1 section per eye was conducted. Common observations in monkeys examined extensively and in historical controls were limited to lymphocytic or mononuclear cell infiltrations of the uvea and/or conjunctiva/sclera and, less commonly observed, melanocytoma of the ciliary body or iris. Findings noted only in monkeys examined extensively consisted of inflammation of the conjunctiva, ora serrata cysts, glial nodules, focal degeneration of the retina, cystoid degeneration of the central retina, ballooning degeneration of the ciliary epithelium, cyst of the ciliary body, and decreased pigmentation of the retinal pigment epithelium. Changes recorded only in historical controls included retinal atrophy and nuclear displacement in the retina. Lesions are discussed and compared with pertinent literature.

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Section: Discussionmentioning

confidence: 99%

Spontaneous Findings in the Eyes of Cynomolgus Monkeys (Macaca fascicularis) of Mauritian Origin

Woicke

Hailé²,

Mysore

et al. 2018

Toxicol Pathol

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“…Although toxicity data have been published with a similar construct at 2 × 10 14 vg/kg in the rhesus monkey, 5 establishing a dose–response capped at 10 14 vg/kg in the cynomolgus monkey was needed to extrapolate these data in a species commonly used for regulatory toxicology, considering the variability of response across species 10 and, for a given species, based on geographical origin. 11 …”

Section: Methodsmentioning

confidence: 99%

Biodistribution and Tolerability of AAV-PHP.B-CBh-SMN1 in Wistar Han Rats and Cynomolgus Macaques Reveal Different Toxicologic Profiles

et al. 2022

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Recombinant adeno-associated viruses (AAVs) have emerged as promising vectors for human gene therapy, but some variants have induced severe toxicity in Rhesus monkeys and piglets following high-dose intravenous (IV) administration. To characterize biodistribution, transduction, and toxicity among common preclinical species, an AAV9 neurotropic variant expressing the survival motor neuron 1 ( SMN1 ) transgene (AAV-PHP.B-CBh- SMN1 ) was administered by IV bolus injection to Wistar Han rats and cynomolgus monkeys at doses of 2 × 10 13 , 5 × 10 13 , or 1 × 10 14 vg/kg. A dose-dependent degeneration/necrosis of neurons without clinical manifestations occurred in dorsal root ganglia (DRGs) and sympathetic thoracic ganglia in rats, while liver injury was not observed in rats. In monkeys, one male at 5 × 10 13 vg/kg was found dead on day 4. Clinical pathology data on days 3 and/or 4 at all doses suggested liver dysfunction and coagulation disorders, which led to study termination. Histologic evaluation of the liver in monkeys showed hepatocyte degeneration and necrosis without inflammatory cell infiltrates or intravascular thrombi, suggesting that hepatocyte injury is a direct effect of the vector following hepatocyte transduction. In situ hybridization demonstrated a dose-dependent expression of SMN1 transgene mRNA in the cytoplasm and DNA in the nucleus of periportal to panlobular hepatocytes, while quantitative polymerase chain reaction confirmed the dose-dependent presence of SMN1 transgene mRNA and DNA in monkeys. Monkeys produced a much greater amount of transgene mRNA compared with rats. In DRGs, neuronal degeneration/necrosis and accompanying findings were observed in monkeys as early as 4 days after test article administration. The present results show sensory neuron toxicity following IV delivery of AAV vectors at high doses with an early onset in Macaca fascicularis and after 1 month in rats, and suggest adding the autonomic system in the watch list for preclinical and clinical studies. Our data also suggest that the rat may be useful for evaluating the potential DRG toxicity of AAV vectors, while acute hepatic toxicity associated with coagulation disorders appears to be highly species-dependent.

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“…For example, cynomolgus monkeys (Macaca fascicularis) of Mauritian, Indian, or Chinese origin have differences in immune responses and background incidence of tissue inflammatory cell infiltrates that have been attributed to differences in their genetics. [40][41][42]…”

Section: Nonhuman Primatesmentioning

confidence: 99%

Scientific and Regulatory Policy Committee Points to Consider*: Approaches to the Conduct and Interpretation of Vaccine Safety Studies for Clinical and Anatomic Pathologists

et al. 2019

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The design and execution of toxicology studies supporting vaccine development have some unique considerations relative to those supporting traditional small molecules and biologics. A working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee conducted a review of the scientific, technical, and regulatory considerations for veterinary pathologists and toxicologists related to the design and evaluation of regulatory toxicology studies supporting vaccine clinical trials. Much of the information in this document focuses on the development of prophylactic vaccines for infectious agents. Many of these considerations also apply to therapeutic vaccine development (such as vaccines directed against cancer epitopes); important differences will be identified in various sections as appropriate. The topics addressed in this Points to Consider article include regulatory guidelines for nonclinical vaccine studies, study design (including species selection), technical considerations in dosing and injection site collection, study end point evaluation, and data interpretation. The intent of this publication is to share learnings related to nonclinical studies to support vaccine development to help others as they move into this therapeutic area. [Box: see text]

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Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Cited by 19 publications

References 45 publications

Spontaneous Findings in the Eyes of Cynomolgus Monkeys (Macaca fascicularis) of Mauritian Origin

Spontaneous Findings in the Eyes of Cynomolgus Monkeys (Macaca fascicularis) of Mauritian Origin

Biodistribution and Tolerability of AAV-PHP.B-CBh-SMN1 in Wistar Han Rats and Cynomolgus Macaques Reveal Different Toxicologic Profiles

Scientific and Regulatory Policy Committee Points to Consider*: Approaches to the Conduct and Interpretation of Vaccine Safety Studies for Clinical and Anatomic Pathologists

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