Publication / Source: Neuro Central
Authors: Sharon Salt, Editor
In this ‘Ask the Experts’ series, we’ve brought together a panel of researchers to discuss gene therapies in neurological diseases in a two-part discussion. How far has the development of gene therapies for neurological diseases come in the last few years? What technical challenges must be overcome before gene therapies are a practical treatment approach for neurological disorders? With gene therapies becoming a rapidly emerging platform for treatment, our experts address these questions and more.
Bringing together insights from research and academia, our experts are Amber Southwell (University of Central Florida, FL, USA) and Krystof Bankiewicz (University of California, San Francisco, CA, USA). Take a look at the first installment of this discussion below, which explores the challenges of gene therapies for neurological disorders and the future direction of the field.
You can also view Part I of the discussion here, which delves deeper into what gene therapies are currently in development for neurological diseases, the design and execution of experiments involving gene therapy, and how to determine the best delivery vehicle to use.
1.What technical challenges must be overcome before gene therapy will be a practical approach to treating neurological diseases?
Amber Southwell: The greatest technical challenge for gene therapy is delivery. For many CNS disorders, broad distribution of a therapeutic is required for efficacy. This is relatively easy to achieve in rodent models for preclinical studies, but considerably more difficult in the much larger and more complex human brain and spinal cord. Antisense oligonucleotides (ASOs) that are delivered naked into CSF distribute evenly throughout the rodent CNS, but not through non-human primate or human brains.
In these larger systems, ASO concentrations in superficial structures that are in greater contact with CSF, such as the cortex, are much higher than those achieved in deeper brain structures, like the basal ganglia, which mediate pathogenesis of many CNS motor disorders. The opposite problem is seen for virally delivered therapies where deep structures can easily be targeted by intracranial injection, but broad distribution, particularly in the cortex where viral particles tend to spread along layers rather than uniformly, is not possible with current delivery technology.
Furthermore, both intrathecal and intracranial delivery are invasive and associated with greater risk than peripheral delivery. Substantial effort to improve delivery for CNS gene therapy strategies is ongoing. Adeno-associated virus capsids are being engineered for enhanced and selective brain delivery after intravenous injection. Systemic and intranasal delivery strategies using nanoparticle and exosome carriers are in development. Additionally, medical devices for intra CNS infusion have been developed to enhance delivery of various gene therapy modalities.
Krystof Bankiewicz: There are a couple of major issues that come to mind straight away, large-scale vector production being just one. I think this is becoming a major issue because production is very technical and very few can do it correctly. Even if large-scale vector production is achieved, reproducibility for each production run can vary somewhat. This is a big challenge in terms of getting the production of these viral vectors under full control.
I think that the other issue surrounds delivery route – that is, fully understanding how to target the regions and the type of cells with the therapeutic vector. As I mentioned earlier on, this has to be very clearly understood and made highly reproducible.
2.How are issues relating to effective design, enhanced biological activity and efficient target delivery being addressed in relation to gene therapy?