[iNOVA4Health] Towards routine manufacturing of gene therapy drugs – requirements for further improvements – example: AAV

Seminar

Title: Towards routine manufacturing of gene therapy drugs – requirements for further improvements – example: AAV

Speaker: Otto-Wilhelm Merten

Affiliation: GENETHON, France

Abstract:

With the recent marketing authorization of several gene therapy treatments based on AAV and MLV vectors and with those to come in the near future, gene therapy has reached an almost mature state. However, in view of the definite establishment as routine therapeutic treatment, the still existing bottlenecks, in particular, with respect to manufacturing but also quality and potency issues, are immense, at least for certain disorders, and have to be overcome. In the case of AAV vectors, the real break-through for their clinical application and finally marketing authorization was achieved after the establishment of scalable production systems. As an example, the first authorized gene therapy treatment of LPL deficiency (Glybera®) based on AAV1 vectors should be mentioned here because it is produced using the scalable insect cell baculovirus expression system. Since LPL deficiency is an ultra-rare disorder, production scales of several tens of liters are sufficient for the production of the required doses. However, when dealing with less rare diseases or diseases for which whole body treatment are required, such as for the treatment of Duchene Muscular Dystrophy (DMD) or other muscle disorders, such manufacturing scales are insufficient. For instance, based on dog studies, doses of 5x1013-1x1014 vg/kg (Le Guiner et al. 2014, 2017) are expected to be required for the treatment of a DMD patient. Such dose levels need further research dealing with the improvement of manufacturing systems, of purification, of vector quality as well as of vector potency, clearly indicating that this is a multi-task developmental activity.
The present talk will briefly present the different rAAV production systems, their production capacity at this stage as well as vector amounts required for some of the ‘famous’ indications. Since Généthon is developing the baculovirus expression system for the production of AAV vectors, several improvements, with respect to vector quantity (per production run) and quality, developed during the recent years will be presented. Further improvements in particular with respect to vector potency in a liver setting will be briefly touched on. As a perspective, the combination of all improvements will allow an improvement in manufacturing by more than fifty-fold.