Gene therapy: Practical aspects of implementation

Abstract

The first wave of gene therapies for haemophilia submitted for regulatory review utilize a liver-directed approach in which a functional gene copy of factor VIII (FVIII) or factor IX (FIX) is packaged inside a recombinant adeno-associated viral vector (rAAV).Following a single treatment event, these particles are taken up into liver cells, where the rAAV uncoats and delivers the DNA to the nucleus of the cell, where genetic elements that accompany the gene allow for efficient expression and secretion of FVIII or FIX protein into the plasma. An immune response to the vector capsid has been manifest by elevations in common liver enzymes that must be diligently followed postinfusion for weeks and months afterward and if signs of toxicity appear, will trigger a course of immunosuppression. Despite this, the studies have shown that this works in the great majority of individuals and the immunosuppression course is either avoided or short-lived for many. Optimal outcomes in the haemophilia population will be dependent on proper screening assessment and maintenance of liver health prior to consideration of gene therapy, close short-term follow up and implementation of immunomodulatory strategies to identify and manage liver toxicity and preserve durable transgene expression. This review proposes best practices to assist clinical teams with overcoming the challenges this platform of therapy poses to the traditional clinical care models and infrastructure within the haemophilia treatment centres (HTCs) who will be coordinating the patient's journey through this potentially transformative therapy. K E Y W O R D Sgene therapy, haemophilia treatment centre, immunosuppression, infrastructure, liver health LIVER HEALTH, SCREENING AND SHORT-TERM FOLLOW-UPSeveral hepatic considerations are relevant in the context of gene therapy as not uncommonly, such patients may have underlying liver disease at baseline or have hepatic abnormalities while undergoing therapy with the attendant long-term risk of hepatocellular carcinoma (HCC), a potential concern in patients undergoing gene therapy. The common hepatic conditions that are encountered in the general pop-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

From a bispecific monoclonal antibody to gene therapy: A new era in the treatment of hemophilia A

“…Gene therapy uses a functional gene copy that encodes FVIII (ref. 58 ). It is packaged inside a recombinant adeno-associated vector or lentiviral vector 57,58 .…”

“…58 ). It is packaged inside a recombinant adeno-associated vector or lentiviral vector 57,58 . Currently, the most used viral vector is the adenovirus because the gene delivered by it does not integrate into the subject's genome and has a low immunogenicity 59 .…”

“…After a single dose, these particles reach liver cells, where the viral vector uncoats and delivers the DNA fragment to the nucleus of the hepatocyte. Genetic elements that are associated with the genes are involved in the appropriate expression and secretion of FVIII protein into the plasma 58 . An ideal gene therapy should be based on minimizing the amount of vector administered and decreasing the number of adverse events without reducing the efficacy of the protein expressed 63 .…”

“…Immune responses can appear against the viral capsid, the vector's nucleic acid, other elements that contaminate the vector, excipients, or the transgene product encoded by the vector 67 . An immune response to the vector capsid can be manifested by an increase in common liver enzymes 58 . The presence of toxicity correlates with the T-cell response to the viral capsid, which justifies the need for immunosuppression 68 .…”

Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies

“…(iv) Tropism/Vector Biodistribution: Given these afore-detailed limitations and the lack of data in human-based model systems that accurately recapitulate normal physiology, it is not surprising that AAV clinical GT trials are experiencing immunological and/or inflammatory responses and levels of transgene expression that are often lower than what was expected based on preclinical studies ( 31 , 59 – 64 ). Another issue that has hampered the translation of AAV vectors from animal models into human patients is the marked species-species differences that exist in AAV vector tropism ( 65 ), which precludes extrapolation of results between species and raises the critical question of how accurately even the best animal models can predict tropism/vector biodistribution, transduction efficiency, and eventual treatment success in humans.…”