Alessio Cantore

The San Raffaele Telethon Institute for Gene Therapy

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Co-Authors

Luigi Naldini

The San Raffaele Telethon Institute for Gene Therapy

Andrea Annoni

The San Raffaele Telethon Institute for Gene Therapy

Michela Milani

Istituti di Ricovero e Cura a Carattere Scientifico

Thierry VandenDriessche

KU Leuven

Marinee Chuah

KU Leuven

Fabio Russo

The San Raffaele Telethon Institute for Gene Therapy

Timothy C. Nichols

University of North Carolina at Chapel Hill

Mauro Biffi

The San Raffaele Telethon Institute for Gene Therapy

Armando D’Angelo

University of Augsburg

Patrizia Della Valle

Vita-Salute San Raffaele University

Cooperative Institutions

Istituti di Ricovero e Cura a Carattere Scientifico

107

Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

Vita-Salute San Raffaele University

The San Raffaele Telethon Institute for Gene Therapy

University of Milan

IRCCS Ospedale San Raffaele

Cambridge University Press

San Raffaele University of Rome

Inserm

University of Bologna

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Spatio-temporal dynamics of the liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and editing

Research Square (Research Square) (2023)

Alessio Cantore Francesco Starinieri Michela Milani Stefano Beretta Cesare Canepari

Abstract The liver is a central organ for metabolism and hepatocytes are the main cell type responsible for most of its functions. Several previous studies investigated the cell types involved in tissue homeostasis and regeneration 1–4 , however the mechanisms underlying post-natal liver growth and establishment of the mature hepatocyte phenotypes remain to be fully understood. Here we investigate liver tissue dynamics in mice during growth and adulthood, by spatial transcriptomics 5 , clonal analysis, and lineage tracing. We observe progressive establishment of metabolic zonation of hepatocytes following weaning, with specification of the centrilobular identity only in adults. We report that only a fraction of hepatocytes proliferates in the newborn liver, generating most of the adult tissue and that preferential genetic modification (either gene transfer or gene editing) of the more proliferating hepatocytes allows expansion of the genetically engineered liver area, stably maintained throughout tissue homeostasis. We also describe age-dependent differences in the efficiency and distribution of lentiviral in vivo gene delivery, with higher efficiency of gene transfer in young compared to adult animals and a skewed localization within the liver lobule. We identify high proteasome activity in the peri-central lobular area as the major determinant of the observed outcome and successfully revert it by proteasomal inhibition before gene transfer. Overall, our findings provide new insights into the spatio-temporal dynamics of the liver during post-natal growth and hepatocyte heterogeneity, which extends our understanding of liver biology and have important implications for therapeutic applications.

Lobules of liver

Liver Regeneration

10.21203/rs.3.rs-3138832/v1

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Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates

Research Square (Research Square) (2021)

Michela Milani Cesare Canepari Tongyao Liu Mauro Biffi Fabio Russo

Abstract Liver gene therapy with adeno-associated viral (AAV) vectors delivering a clotting factor transgene into hepatocytes has shown multi-year therapeutic benefit in adults with hemophilia. However, anti-AAV pre-existing immunity and the mostly episomal nature of AAV vectors, currently challenges application of AAV-vector mediated liver gene therapy to people with anti-AAV neutralizing antibodies and young pediatric patients. We have developed lentiviral vectors (LV), which integrate in the host cell genome, which achieve stable and efficient liver gene transfer in mice, dogs and non-human primates (NHP), by intravenous (i.v.) delivery. Here we show long-term coagulation factor VIII (FVIII) activity and restoration of hemostasis, by LV i.v. gene therapy to newborn and adult hemophilia A mice and normal-range FVIII activity in NHP, paving the way for potential clinical application.

Factor IX

Clotting factor

Adeno-associated virus

10.21203/rs.3.rs-858195/v1

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Gene transfer and genome editing for familial hypercholesterolemia

Frontiers in Molecular Medicine (2023)

Cesare Canepari Alessio Cantore

Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by high circulating low-density lipoprotein (LDL) cholesterol. High circulating LDL cholesterol in FH is due to dysfunctional LDL receptors, and is mainly expressed by hepatocytes. Affected patients rapidly develop atherosclerosis, potentially leading to myocardial infarction and death within the third decade of life if left untreated. Here, we introduce the disease pathogenesis and available treatment options. We highlight different possible targets of therapeutic intervention. We then review different gene therapy strategies currently under development, which may become novel therapeutic options in the future, and discuss their advantages and disadvantages. Finally, we briefly outline the potential applications of some of these strategies for the more common acquired hypercholesterolemia disease.

Dysfunctional family

Pathogenesis

Gene transfer

10.3389/fmmed.2023.1140997

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Citations (4)

Hepatocyte‐targeted expression by integrase‐defective lentiviral vectors induces antigen‐specific tolerance in mice with low genotoxic risk

Hepatology (2011)

Janka Mátrai Alessio Cantore Cynthia C. Bartholomae Andrea Annoni Wei Wang

Abstract Lentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity. Conclusion: IDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis. (Hepatology 2011;)

Insertional mutagenesis

Factor IX

Expression cassette

10.1002/hep.24230

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Citations (133)

Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes

Science Translational Medicine (2021)

Anne Vonada Amita Tiyaboonchai Sean Nygaard Jeffrey Posey A. Mack Peters

Acetaminophen treatment can be used to increase transgene expression for liver gene therapy into the therapeutic range in mice.

Repopulation

Acetaminophen