San Raffaele Telethon Institute for Gene Therapy

Goal 3. Broaden application of lentiviral vectors to in vivo gene therapy

SR-Tiget Goal 3

HemA/B: Hemophilia A and B; MLD: Metachromatic Leukodystrophy

We envisage that lentiviral vectors (LV) may help addressing some of the current limitations of other gene transfer platforms (i.e. adeno associated vector-based) for in vivo gene delivery targeting the liver or the central nervous system (CNS), thus complementing or even overcoming their reach in addressing relevant unmet medical needs.

Some of the LV advantages include:

  1. efficient genomic integration allowing long-term maintenance and transfer of gene correction to the cell progeny, thus potentially providing for sustained lifelong benefit even upon treatment at an early age;
  2. limited pre-existing immunity in the population and low innate cellular and inflammatory response to gene transfer;
  3. large cargo capacity for genetic payloads and regulatory elements.

On the other hand, some outstanding safety concerns remain and while we have continued to address them in comprehensive preclinical studies, they might be fully addressed only upon the first clinical testing. The concern for the genotoxic risk of LV integration into hepatocytes has been tempered by the positive results of preclinical studies in sensitized models and can be conceivably alleviated by their safety record in hematopoietic stem cell gene therapy (HSC GT). However, this will be ultimately addressed only by careful monitoring of the patients in a first-in-human trial, also by exploiting novel readouts based on cell-free plasma DNA.

The same is true for the risk of eliciting adverse immune response to the transgene product. Manufacturing of adequate LV amount and purity for safe intravenous administration remains challenging. Furthermore, whether intravenous administration of LV to young individuals with a rapidly growing liver may be conducive to long-term stable gene expression in humans depends on several factors. LV biodistribution and transduction of different cell types upon intra-CNS administration is similarly subject to several factors and may not be easily modeled in limited and expensive non-human primate studies.

Leveraging on long-standing evidence of efficacy and safety obtained in a series of preclinical studies in small and large animal models we will continue to pursue the following two applications of LV gene transfer in vivo:

  • systemic, liver-directed administration for the GT of hemophilia and selected inborn metabolic diseases
  • intracerebral gene transfer for neurodegenerative storage diseases such as metachromatic leukodystrophy.

We will both fine tune each platform to optimize safety, efficiency and durability of gene transfer and investigate the biological features of the target cells and tissue and the impact of the underlying disease that may affect such outcomes. Clinical translation will be pursued within the framework of collaboration with industry, providing the required complementary expertise and resources.

Main Principal Investigators involved: CANTORE, GRITTI, KAJASTE.