Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models

Robert Allen Kaiser, Clara Teresa Nicolas, Kari Lynn Allen, Jennifer Anne Chilton, Zeji Du, Raymond Hickey, Joseph Benjamin Lillegard

Research output: Contribution to journalArticle

Abstract

General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (109 TU/mouse) or in combination with DEN/CCl4 presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl4 induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl4-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.

Original languageEnglish (US)
Pages (from-to)57-66
Number of pages10
JournalHuman Gene Therapy Clinical Development
Volume30
Issue number2
DOIs
StatePublished - Jun 1 2019

Fingerprint

Toxicology
Liver
Wounds and Injuries
Body Weight
Tyrosinemias
Safety
Diethylnitrosamine
Carbon Tetrachloride
alpha-Fetoproteins
fumarylacetoacetase
Weight Gain
Regeneration
Hepatocytes
Research Design
Necrosis
Animal Models
Immunohistochemistry
Neoplasms

Keywords

  • gene therapy
  • hereditary tyrosinemia type 1
  • lentiviral vectors
  • toxicology
  • tumorigenicity

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models. / Kaiser, Robert Allen; Nicolas, Clara Teresa; Allen, Kari Lynn; Chilton, Jennifer Anne; Du, Zeji; Hickey, Raymond; Lillegard, Joseph Benjamin.

In: Human Gene Therapy Clinical Development, Vol. 30, No. 2, 01.06.2019, p. 57-66.

Research output: Contribution to journalArticle

Kaiser, Robert Allen ; Nicolas, Clara Teresa ; Allen, Kari Lynn ; Chilton, Jennifer Anne ; Du, Zeji ; Hickey, Raymond ; Lillegard, Joseph Benjamin. / Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models. In: Human Gene Therapy Clinical Development. 2019 ; Vol. 30, No. 2. pp. 57-66.
@article{297dcf1c3a8745dead93ac8432c17964,
title = "Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models",
abstract = "General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (109 TU/mouse) or in combination with DEN/CCl4 presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl4 induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl4-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.",
keywords = "gene therapy, hereditary tyrosinemia type 1, lentiviral vectors, toxicology, tumorigenicity",
author = "Kaiser, {Robert Allen} and Nicolas, {Clara Teresa} and Allen, {Kari Lynn} and Chilton, {Jennifer Anne} and Zeji Du and Raymond Hickey and Lillegard, {Joseph Benjamin}",
year = "2019",
month = "6",
day = "1",
doi = "10.1089/humc.2018.249",
language = "English (US)",
volume = "30",
pages = "57--66",
journal = "Human gene therapy. Clinical development",
issn = "2324-8637",
publisher = "Mary Ann Liebert Inc.",
number = "2",

}

TY - JOUR

T1 - Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models

AU - Kaiser, Robert Allen

AU - Nicolas, Clara Teresa

AU - Allen, Kari Lynn

AU - Chilton, Jennifer Anne

AU - Du, Zeji

AU - Hickey, Raymond

AU - Lillegard, Joseph Benjamin

PY - 2019/6/1

Y1 - 2019/6/1

N2 - General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (109 TU/mouse) or in combination with DEN/CCl4 presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl4 induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl4-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.

AB - General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (109 TU/mouse) or in combination with DEN/CCl4 presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl4 induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl4-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.

KW - gene therapy

KW - hereditary tyrosinemia type 1

KW - lentiviral vectors

KW - toxicology

KW - tumorigenicity

UR - http://www.scopus.com/inward/record.url?scp=85067557122&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067557122&partnerID=8YFLogxK

U2 - 10.1089/humc.2018.249

DO - 10.1089/humc.2018.249

M3 - Article

C2 - 30860398

AN - SCOPUS:85067557122

VL - 30

SP - 57

EP - 66

JO - Human gene therapy. Clinical development

JF - Human gene therapy. Clinical development

SN - 2324-8637

IS - 2

ER -