A team of researchers from institutions in Italy and the U.S., in conjunction with several corporate entities, has found that adding a protein to lentiviral vectors can protect them from an immune system attack.
With the first marketing authorization of an AAV1 vector for the treatment of lipoprotein lipase deficiency (Glybera®) in Europe,1 viral vector-based gene therapy is more and more rapidly evolving towards the routine treatment of rare and acquired diseases for which different viral vectors systems are available.
Depending on the purpose of the treatment as well as the target cells or tissues to be treated, one or the other vector system is preferable.
In case of dividing, tissues or cells integrating vectors are required for the long-term expression of the transgene.
Traditionally, retroviral vectors (in a large sense) are the vectors of choice because they lead to a stable integration of the transgene to be expressed.
Mainly two different retroviral vector systems have been developed: γ-retroviral vectors derived from murine leukemia viruses (MLV)2 and lentiviral vectors (LV) mainly derived from HIV-1.3
In the past, many clinical trials based on the use of MLV vectors were successful4 and although these vectors are still used, the general tendency is towards the use of LV vectors.
Different reasons can be quoted for this shift: (i) in contrast to γ-retroviral vectors, LVs are able to transduce nondividing cells because they can translocate across the nuclear membrane5; (ii) their integration patterns are different from MLV vectors and seem to be less risky with respect to insertional mutagenesis6; and (iii) they can be produced at high vector titer.
These are the main reasons why there is a clear transition from the use of MLV to LV vectors though the overall manufacturing conditions for LV vectors have not yet reached their maximal potential and the level of those used for MLV vectors.
LV vectors have been used successfully in clinical trials, in a first instance for the treatment of rare diseases, in particular, of primary immunodeficiencies7,8 and in neurodegenerative storage diseases.9,10
However, their application for the treatment of more frequent genetic and acquired diseases, including treatment of β-thalassemia,11 Parkinson’s disease,12 and chimeric antigen receptor-based immunotherapy of cancer,13 has been assessed in clinics with exciting outcomes.
This means that manufacturing technology becomes a critical issue in view of the implementation of these novel therapies for routine use.
In their paper published in the journal Science Translational Medicine, the group describes their work in finding new ways to treat hemophilia and how well their approach worked in monkeys.
Hemophilia impairs the body’s ability to make blood clots, putting people at great risk of bleeding to death from even small injuries.
The heritable condition is thought to arise in people who lack a coagulation factor in their genome.
Currently, scientists are trying to treat people with hemophilia using gene therapies.
One such therapy involves the use of an adeno-associated virus (AAV) to deliver a gene that expresses the missing coagulation factor.
Unfortunately, most people develop an immune response to AAV by the time they reach adulthood.
In this new effort, the researchers have taken another approach using a different kind of vector.
The approach used lentiviral vectors (LVs) instead of an AAV; derived from HIV, the LV is less prevalent in humans, and therefore provides a better gene therapy option.
But the researchers found that LVs tend to be removed from the body by phagocytes (white blood cells) before they can deliver their therapeutic payload to the target.
To get around this problem, the researchers used a protein called CD47.
Prior research found that CD47 is capable of avoiding detection and cleansing by phagocytes.
The researchers applied it to the surface of LVs to help the LVs escape detection and subsequent cleansing.
The researchers tested their modified LVs by injecting them into six test monkeys.
They report that the LVs were able to deliver their therapies to their targets (the liver and spleen) and effectively transferred genes to liver cells as planned.
More testing is required, but the researchers suggest their approach could result in lower dose treatments for hemophilia, which they note would likely reduce side-effects and lower production strain on manufacturers.
Fluorescent lentiviral vectors (LV, green) were rapidly taken in by liver macrophages (KC, red) after administration to mice. Credit: M. Milani et al., Science Translational Medicine (2019)
More information: Michela Milani et al. Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates, Science Translational Medicine (2019). DOI: 10.1126/scitranslmed.aav7325
Journal information: Science Translational Medicine
