Gene Therapy in Epilepsy: Preliminary Considerations


In our previous articles we have discussed a number of therapeutic options in development for the treatment of epilepsy. We have discussed, for example, the viewpoint that epilepsy may be an inflammatory condition, and hence should be treated as such.

We now begin to discuss some of the more novel approaches being studied to treat epilepsy, beginning with gene therapy. Before delving into specific approaches in epilepsy, there are a few general gene therapy issues which need to be considered:

  1. Delivery & route of administration
  2. Therapeutic Goals
  3. Risk/benefit versus alternatives (i.e., implants & surgery)

Delivery & Route of Administration

Intramuscular – In theory, intramuscular administration of a gene therapy would be the simplest route of administration. Not only is intramuscular administration already very common, it is also well suited for gene therapy. This is because some vectors, e.g. AAV1 vectors, have a predisposition for muscle cells. Indeed, this is the rationale for using the AAV1 vector for the delivery of the gene encoding the LPL gene for the treatment of lipoprotein lipase deficiency (Glybera®, alipogene tiparvovec, uniQure).

However, as demonstrated by the dosing scheme for Glybera®, this predisposition does not necessarily result in efficient, straightforward administration. Glybera® is administered via a one-time procedure consisting of sixty intramuscular injections in the legs while the patent is under anesthesia. Further, the recipient must undergo immunosuppression prior to and for 12 weeks after administration.

Considering that lipoprotein lipase deficiency is associated with pancreatitis, diabetes, and other serious conditions, a one-time procedure with the potential to cure the disease seems well worth it, irrespective of the $1 million cost. Regardless, this demonstrates that “simple” intramuscular gene therapy may not be as simple or even as feasible as we would like for other conditions.

Intravenous – Intravenous administration of gene therapy is perfect for blood-born conditions, such as the various forms of hemophilia. This is because liver hepatocytes are already set up to gather and process blood-borne viruses. Thus, the intravenous administration of a viral vector carrying a desired gene will be naturally taken up by hepatocytes.

            However, intravenous infusion of viral particles runs the major risk of triggering an acute inflammatory response. Barring that, pre-existing antibodies may recognize the viral vector, thereby clearing the vector and rendering the therapy unsuccessful. Regardless of these risks, a number of clinical trials are underway for the treatment of hemophilia. In some cases, success is defined not necessarily as a total cure, but in a reduction in the number of administrations of prophylactic factor replacement therapies required to manage the disease.

This is an important point from an epilepsy perspective. In other words, in case gene therapy does not render a total cure for some patients, the therapy may at least simplify disease management in some way, i.e., a major reduction in the number of seizures per month, or the avoidance or delay of surgery, or increased responsiveness to oral medications, or even simply a reduction in symptoms, then the gene therapy could be considered a success.

For both intramuscular and intravenous administration, successful delivery of a gene to the muscle or plasma does not address the issue of getting that protein across the blood brain barrier to the hippocampus of the brain, where it is actually needed. Thus, some sort of additional target-specific carrier would have to be synthesized along with the protein in order to get it into the brain…a feat with unquestionable complexity and risk. This assumes that this protein can even survive proteolysis in the plasma.

Intracranial – The intracranial delivery of gene therapies for the treatment of various CNS conditions is not a totally new concept. Enzyme deficiencies, cancers, neurodegenerative diseases, and other CNS conditions can claim to have gene therapy as part of their development pipeline.

            For example, the intrastriatal delivery of a lentiviral-based gene therapy for the treatment of Parkinson’s disease recently completed a Phase I/II clinical trial. Interestingly, improvement in motor behavior was observed in all patients across all three dosing ranges, suggesting the gene therapy has promise. Other neurodegenerative conditions which may benefit from direct cranial delivery of gene therapies include amyotrophic lateral sclerosis and Alzheimer’s disease.

            Brain cancers, such as glioblastoma, are an obvious choice for the development of gene therapy-based approaches. In fact, a number of different approaches to treat glioblastoma are amenable to gene therapy (Reviewed by Kane, et al.). For example, oncolytic virotherapy can be used to trigger tumor cell lysis. The resulting bystander effect may also trigger additional tumor cell killing. Again, getting a sufficient dose to the tumor site will likely require direct introduction to the cancerous tissue area as part of a surgical procedure. Stereotaxic approaches could be used in the clinical setting to ensure focused delivery of gene therapies.

Therapeutic Goals

            When considering gene therapy for the treatment of epilepsy, there are two general categories of goals: Anti-epileptogenic (stopped or even reversed pathophysiological progression) and anti-epileptic (increasing seizure threshold and reduction in seizure severity and mortality). Various gene therapies have been proposed which try to address these different goals. Perhaps in the future, epileptologists will have a suite of gene therapies to choose from in order to personalize the treatment to the individual patient’s condition. For example, Bovolenta et al. described a gene therapy which delivers FGF-2 and BDNF in an HSV-1 vector. In their study, this gene therapy reduced the neuroinflammation associated with an epileptogenic lesion in a rat model. Such a system could be considered not only anti-epileptic, but disease modifying as well.

            Anti-epileptic gene therapies may not modify the underlying disease, but they can (in theory) reduce seizure frequency and severity. Indeed, the overwhelming number of proposed gene therapy approaches in epilepsy have this goal in mind (Reviewed by Simonato). Like the FGF-2/BDNF combination described previously, a combination of NPY and Y2 in an AAV vector system has been described. This combination was shown to work better than NPY alone. These examples illustrate the potential flexibility and creativity associated with gene therapy. While polypharmacy is usually discouraged, there may be instances where the administration of multiple genes will confer better therapeutic results versus a single gene.

Risks versus Alternatives

            Approximately 30% or more of epileptic patients continue to experience frequent seizures while on conventional anti-epileptic pharmacotherapy. For a significant portion of these patients who have tried various drug cocktails and nerve stimulators, surgery is the only remaining option. When compared to these two options, one can argue that the stereotaxic administration of a gene therapy intracranially is a preferable option. However, vector-associated risks and adverse events, such as immune reactions, cannot be ignored. Fortunately, we now have one gene therapy on the market, perhaps with a riskier profile than what we would anticipate from a gene therapy for epilepsy. The learnings from the approval of Glybera® will guide researchers developing gene therapies for epilepsy and other conditions for years.

Looking Back…Looking Forward

Industry and academia have made great strides in the development of gene therapies to treat a variety of condition. We now have a gene therapy product on the market, with many more to follow. Yet this success does not imply that all of the challenges associated with gene therapy have been solved. What it does imply is that gene therapy may lend itself to certain conditions or sites more so than others.

From an epilepsy perspective, intramuscular and intravenous approaches are obviously not feasible, at least in the foreseeable future. However, given the experience gained by the stereotaxic administration of gene therapies for glioblastoma, it is conceivable that this approach can be used to treat other CNS conditions, including epilepsy.

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