Neurology Central

Ask the Experts: Gene therapies in neurological diseases (Part I: development, design and delivery)

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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 looks at 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.
Additionally, take a look at part II of the discussion here, which delves deeper into the challenges of gene therapies for neurological disorders and the future direction of the field.

1.What gene therapies are currently in development for neurological diseases?

Krystof Bankiewicz: There is a wide spectrum of targets currently being worked on, ranging from neurodegenerative disorders, such as Parkinson’s, Alzheimer’s and Huntington’s disease (HD), all the way to ophthalmic disorders, including retinal dystrophy. In addition to these, there are several gene therapy programs in development for lysosomal storage disorders. Many of those mentioned above are in clinical trials.

Amber Southwell: For HD, there are currently several strategies in development to reduce the mutant protein. HD is uniquely caused by expansion of a polyglutamine-encoding CAG trinucleotide repeat tract in the huntingtin (HTT) gene. Affected individuals are predominately heterozygous, but rare homozygous cases have been studied. The HTT protein is required for brain development but its lifelong function is controversial. Some believe that HTT is critical to maintenance of neuronal health throughout life, while others believe that it is entirely expendable in the adult brain. Thus, there are both non-selective total HTT lowering and allele-specific mutant HTT lowering strategies in development.

Both non-selective and selective antisense oligonucleotide (ASO) HTT suppression drugs are currently being evaluated in clinical trials, with non-selective in Phase III and selective in Phase I/IIa. These nucleic acid biological drugs are delivered directly into patient cerebrospinal fluid with no viral or lipid carrier. Additionally, an intracranial virally delivered miRNA that non-selectively suppresses HTT has recently been granted investigational new drug status by the US FDA with a clinical trial soon to follow. Another non-selective miRNA and an allele-specific zinc finger transcriptional suppressor, both virally delivered into the brain parenchyma, are in advanced preclinical development. Finally, there are multiple CRISPR/Cas9-based HTT gene inactivation strategies in early preclinical development.

2.What determines the success of a gene therapy?

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