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.
“Antisense oligonucleotides 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?
KB: This brings up the difficulty of the therapeutic dose. Typically, as a physician, you prescribe medication based on certain principles, such as the severity of the disease, the type of patient in terms of gender, sex, weight or surface area. Here, we have no idea how to prescribe gene therapy a priori. Thus, this is not something that is fully understood, and is a huge issue in terms of how to really correlate the dose of the gene therapy that we would like to deliver to expected therapeutic effect. This has to do with the fact that we can only administer the gene therapy drug once, which is obviously a huge selling point in gene therapy, as the patient is not being subjected to repeated administration of the therapy. However, this presents a challenge because one has to have the dose correctly calculated and I think that this issue is not well understood at this point and has to do with the fact that selectivity and levels of gene expression are not fully controlled.
3.Will the high cost of gene therapy limit its availability to patients?
AS: Available gene therapies are prohibitively expensive. While sometimes covered by insurance, these costs are not sustainable for individuals or insurance companies. Part of the reason for this is the cost of developing gene therapies, which is staggering. These approaches are much more complex and expensive than traditional small molecule therapies. One approach to reducing gene therapy costs may be to extend patent protection periods for gene therapies compared to small molecule therapies. This would allow the companies that develop therapies an extended interval to recoup development costs prior to less expensive generics being made available.
“Right now, the prices are astronomical, and this is based on, ‘What is the burden of the cost of caring for a patient with a given disease?’”
KB: It most definitely will. We have to remember that, of course, those who develop these treatments have in mind developed countries that could perhaps carry the burden of very highly priced gene therapy. The rest of the world, on the other hand, may not have this available to those who need the treatment. I think there is a huge debate with the regulators in the pharmaceutical and biotechnology industries. Right now, the prices are astronomical, and this is based on, ‘What is the burden of the cost of caring for a patient with a given disease?’
I think that this doesn’t usually reflect the reality of developing these types of treatments. Maybe at some point there will be some competition, just like with generics, to lower the cost. However, at this point, there is very little hope of this really happening. Take retinal dystrophy as an example, the gene therapy treatment has been priced at approximately USD $500K for each eye. For spinal muscular atrophy, the gene therapy from Novartis (Basel, Switzerland) is proposed to be going at approximately USD $4 million or more – so these are really high price tags for rare disorders.
Perhaps if we show good effectiveness for these therapies, there may be some way to lower the cost.
4.What are the ethical issues surrounding gene therapy?
KB: I think there are a number of ethical issues. One, of course, is the fact that we are introducing a gene that makes a permanent change to a cellular function, which we can’t reverse. This is a big ethical issue but usually the burden of the disease is so high that it often justifies this type of treatment.
At the stage we are currently at with gene therapy, it is easier to justify from an ethical point our interventions because we are just expressing a single gene that is not functioning properly. We’re not implementing any gene editing because that would take our approach to a much different ethical level. That said, one could edit many genes with this type of technology, even those that are not perhaps related to the disease. I think those ethical issues will become more and more prominent.
“At the stage we are currently at with gene therapy, it is easier to justify from an ethical point our interventions because we are just expressing a single gene that is not functioning properly.”
You may have heard information around 1–2 months ago disclosed by a Chinese scientist, where embryos were edited in order to change expression of genes. In this case, there were genes that encoded resistance for the HIV/AIDS virus, and this shows that technology can evolve to the point where there are many unresolved ethical issues. On the surface, one might consider this to be a good thing, but the gene that was altered did not evolve merely to endow us with susceptibility to HIV. It has other functions that may also be very important for the future health of the individual in question. Unintended consequences are a very real danger.
5.Certain forms of administrations for gene therapies require higher total doses to achieve transduction. Could the scale of manufacturing for these therapies be efficient enough to support these greater material requirements?
KB: Most definitely. In terms of adeno-associated virus production and strategy, there have been tremendous advances. Current production methods allow us to produce much greater numbers of viral particles. Thus, one campaign can really support a pretty sizable clinical trial. I think, as this becomes more mainstream and more gene therapy facilities are being erected to support these clinical trials and products, we will benefit from more efficient and cheaper means of producing gene therapy products.
This then brings the issue of delivery strategy again, as there is a tremendous difference between inserting a needle into the brain as opposed to giving intravenous administrations of the product. Of course, it’s cheaper to deliver via intravenous route and more expensive to do it surgically. However, as the field progresses, I think both strategies will become more cost-efficient.
6.Tropism differences across species may pose particular challenges for engineering and selection for human therapeutic use. How could this be overcome?
KB: This again is an important question. We have multiple examples of tropism in lower species not being representative of what’s happening in humans and non-human primates – I’ve witnessed it myself many times. Both the EMA and US FDA mandates that a lot of experiments be carried out before applying this technology to patients in non-human primates, and this is to really ensure the safety of the patients.
There are also immune responses to some of the transgenes and some of the particles. This is a tremendous challenge and I think having information derived from non-human primates really lowers the uncertainties that one would have with the tropism in the human population.
7.In your opinion, when do you anticipate gene therapy will become a viable treatment option for neurological diseases?
“We now have approved virally delivered systemic gene therapy, and I would predict that we will have approved CNS viral gene therapy within a decade.”
AS: ASO gene therapy has already become a viable treatment option for neurological disease. At the end of 2016 a Phase III clinical trial of nusinersen, a splice altering ASO, was halted for efficacy by the FDA, after which the drug was approved. This is the only approved drug for the treatment of spinal muscular atrophy. Additionally, one ASO is in Phase III and two ASOs are in Phase I/IIa for the treatment of Huntington’s disease (HD). Finally, an ASO has demonstrated both safety and preliminary therapeutic efficacy for the treatment of amyotrophic lateral sclerosis. Virally delivered gene therapies have not yet reached this point, though there have been substantial recent advances. We now have approved virally delivered systemic gene therapy, and I would predict that we will have approved CNS viral gene therapy within a decade.
KB: In some instances, it already has. We all consider the eye to be a part of the CNS, so this was a turning point in the sense that people who were affected by retinal dystrophy mutation and lost sight, are regaining it. This is a major triumph for the technology.
As I mentioned previously, a number of rare monogenic disorders will be much more tractable targets from a technological point of view. There is tremendous progress being made. I believe that some of the treatments in Parkinson’s disease and HD, and hopefully Alzheimer’s disease, will prove themselves. However, in this field, nothing happens overnight. We’re talking probably around another 5–10 years before we have several other approved treatments.
8.Where do you see the field progressing in the next 10 years?
KB: I really think that if we were to have this conversation 10 years from now, there would be a long list of approved treatments for brain disorders – I’m absolutely convinced of that. Knowing what’s going on in my own group, and with collaborators, I think we are now at version 2.0 of what we were trying 10–15 years ago.
What we are after is meant to change the course of many disorders in the brain. We just need to have enough patients and convince the regulators that the treatment is working. A number of these trials are rapidly progressing. In 10 years from now, we should have at least 15 approved treatments.
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About the experts
Amber Southwell – University of Central Florida
Amber Southwell is an Assistant Professor at the University of Central Florida, Burnett School of Biomedical Sciences, Division of Neuroscience (FL, USA). She has been working in preclinical therapy development for HD since 2002. In 2009, Amber earned her PhD at the California Institute of Technology (CA, USA) working with Paul Patterson to develop an intrabody gene therapy for HD. From 2009–2016, she did postdoctoral research at the University of British Columbia (Vancouver, Canada) with Michael Hayden where she developed several novel mouse models of HD, a selective mutant huntingtin gene silencing therapy, and a CSF biomarker for brain huntingtin. Amber began her laboratory research group at the University of Central Florida in January 2017, where she continues these studies while also applying her successful strategies for HD to other inherited neurological diseases.
Krystof Bankiewicz – University of California, San Francisco
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.