Hepatic Manifestations Following Gene Therapy

Abstract

Gene therapy involves the introduction of genetic materials, most commonly using viral vectors, to alter gene expression to ameliorate or cure disease symptoms with minimal adverse events. While interest in gene therapy has been on the increase, concerns have arisen about the potential for hepatotoxicity, which arises from diverse mechanisms. While viral vectors can produce dose-dependent hepatotoxicity secondary to integration, immune responses appear to be the primary driving mechanism. A mild increase in aminotransferases is the most common hepatic manifestation, occurring variably in 20%-80%, while there has been rare progress to acute liver failure. The occurrence of hepatotoxicity is unpredictable and can vary depending on patient comorbidities, vector dose, vector type, and degree of immune activation. Pretreatment screening for underlying chronic liver disease and exclusion of advanced fibrosis or cirrhosis using noninvasive tests is essential. Literature on liver biopsy pre- and post-therapy is limited, but small studies show safety in the long term. Immunosuppression, most commonly using corticosteroids, is the first-line modality in management. Approaches vary between prophylactic and reactive strategies, and there remains an absence of consensus on the most appropriate strategies. First-line therapy for a variable duration and dose settles most cases of hepatotoxicity. In selected difficult-to-treat cases, second-line agents (sirolimus, mycophenolate mofetil, and calcineurin inhibitors) are required, while there is no current consensus on the ideal second-line strategy. Intense short-term and extended long-term hepatic monitoring is recommended. Variabilities in presentation and challenges in management strategies mandate a multidisciplinary collaboration with the active involvement of hepatologists/gastroenterologists to optimize liver health.

Keywords: Adenovirus; Corticosteroids; Gene vectors; Hepatotoxicity; Liver injury; Transgene.

Graphical abstract

Figure 1

Timeline depicting the major events in the evolution of gene therapy. ADA, adenosine deaminase; DMD, Duchenne muscular dystrophy; OTC, ornithine transcarbamylase; SCID, severe combined immunodeficiency.

Figure 2

Schematic representation of viral vector-based gene therapy and hepatic implications.

Figure 3

Approaches to the prevention and management of hepatic manifestations: A guide to practitioners. CNI, calcineurin inhibitor; HCC, hepatocellular carcinoma; NIT, noninvasive test.