Neuro Primer: Gene Therapy

By: Justin McMahon

Academic laboratories and biotech companies around the world are racing to develop next-generation therapeutics. At the forefront of this scientific innovation is gene therapy: a medical approach used to treat, or even prevent, genetic disorders.

Pfizer, the multinational pharmaceutical and biotech company, expresses strong support for gene therapy’s promise: “Gene therapy could enable patients to live without the need for ongoing treatments or the burden of daily disease management. We’re going beyond helping people manage their diseases. We want them to thrive in every stage of life” (Pfizer Inc., n.d.).

Gene therapy, and support for its potential to treat or prevent diseases caused by dysfunctional genes, is becoming increasingly popular in the fields of science and medicine. But what is it? How does it work? And who are the ideal candidates to receive such treatment? By the end of this brief overview of gene therapy and its influence on the human condition, you will be well-equipped to engage critically with the buzzing news articles and scientific literature that gene therapy will continue to bring forth.
Science has come a long way in revolutionizing medicine, and the field always seems to find creative ways to approach complex problems. A key roadblock in the treatment of many diseases is the difficulty of designing a drug or therapeutic that not only successfully targets the diseased cells or tissues, but also fixes them. For many diseases, current treatment options might be able to target and even fix the unhealthy cells, but the effects only last for a limited period of time. Wouldn’t it be great if there was an alternative approach that could both target the appropriate cells and have long-lasting, sometimes permanent, effects in a single treatment?

How it works
Admittedly, the term “DNA editing” sounds quite off-putting when discussing disease treatment options. But in reality, not all gene therapies actually “edit” your DNA – most only introduce a healthy copy of the gene so your cells’ machinery can use this functional copy instead of the diseased one (American Society of Gene + Cell Therapy, 2021). If we think of DNA as your body’s biological instructions, this means that most gene therapies simply provide a new, healthy copy of instructions to your cells rather than changing the original copy. Your cells would then “read” these new instructions, resolving the issues caused by the originally-dysfunctional gene, and have these changes available as a blueprint for years post-treatment (Herzog, 2020).

While the majority of currently-available gene therapies work by delivering a functional copy of a gene into a cell, development is underway to create gene therapies that make use of gene editing approaches (Doudna, 2020). In gene editing therapeutics, for example those using CRISPR-Cas systems (which you can learn more about in our infographic!), the original copy of a person’s dysfunctional gene is modified. Rather than a new set of instructions being delivered to the cell, the original copy is revised with the instructed edits. If these edits are made in the DNA of a cell that is capable of cell division, this means that the newly-produced daughter cells will also incorporate these changes going forward.

Gene therapies can target many different types of biological processes: not only can they replace or edit genes, they can also regulate the effects of genes or even instruct a cell to produce an antibody for the immune system to kill. In a situation where the expression of a gene is causing too much RNA and subsequent protein to build up, as is the case with cancers, a gene therapy might tag the extra RNA to be broken down (a process referred to as RNA interference) or instruct the affected cells to produce an antibody for the immune system to recognize and destroy the cells (Deverman et al., 2018).

Similarly to how you need to place an item in an appropriate box or envelope before you are able to ship it from point A to point B, the components of a gene therapy must also be properly packaged in order to efficiently deliver the materials to the correct cells. Viruses are an attractive option as a vehicle for delivering gene therapeutics because of their natural ability to target specific cells and deliver genetic materials. If a virus could be modified to be non-pathogenic but still able to deliver the genetic materials to the correct cells, scientists could use these viruses to treat diseases rather than cause diseases.

Adeno-associated viruses (AAVs) are a class of virus that has become one of the most common approaches to delivering the adjusted genetic blueprints in gene therapeutics – especially for diseases which affect the brain (Wang et al., 2019). Because they are non-pathogenic and are efficient at gene transfer in cells, along with their ability to produce long-term effects, AAVs fit the bill as a promising “viral vector” for gene therapy (Haggerty et al. 2020). AAVs can also be optimized to target only a specific kind of cell. In a disease where a certain gene is dysfunctional, scientists can look at which types of cells express that gene to identify the gene therapy target. We know that different cell types express different proteins, which give cells their different functions. Scientists can use these differences to their advantage by designing unique AAVs that will only target the cell type of interest (Wang et al., 2019).

What types of disorders can be treated?
Many of the available gene therapeutics work to treat cells in the liver, immune system, or even musculoskeletal system: diseases like hemophilia, Adenosine deaminase (ADA) deficiency, and fat metabolism disorder (University of Utah, n.d.). Fewer gene therapeutics are available to treat disorders affecting the central nervous system, though there has been success in improving vision in people with choroideremia – and promising results in the treatment of Parkinson’s disease and Huntington’s disease, among others (Haggerty et al., 2020). However, not all genetically-linked diseases make good candidates for gene therapeutics.

In order for a disorder to be a promising candidate for gene therapy, it must be possible to correct the condition by introducing one or a few functional genes. This means that monogenic disorders – or disorders caused by the mutation(s) of a single gene – are usually the best candidates. However, the human genome contains over 60,000 genes (Nurk et al., 2022): so it is not surprising that most disorders are caused by multiple genes (Lvovs et al., 2012) – we call these disorders polygenic. Because it is so difficult to isolate and treat all of the different genes involved in a polygenic disorder, most of the currently available gene therapies aim to treat rare, monogenic disorders (Rittié et al., 2019).

While monogenic disorders are often the preferred candidates for development of gene therapeutics, analyzing conditions caused by the variation of a single gene is not always as straightforward as you might think. For example, Rett syndrome is a monogenic neurodevelopmental disorder that causes affected children to rapidly lose abilities in coordination and speech (Renieri et al., 2003). But even within the “Rett syndrome gene” (MECP2), it has been shown that there are many different possible mutations that can lead to development of the disease (Sung Jae Lee et al., 2001). There is also the possibility for an individual to have a mutation in MECP2 that does not lead to Rett syndrome onset – but instead to symptoms of other neuropsychiatric disorders. To make seemingly-simple matters all the more complex, there are certainly also cases of children diagnosed with Rett syndrome who do not have mutations in this gene whatsoever (Suter et al., 2014).

Once the disease gene (or genes) is identified, it is important to understand the biology. It is not enough to know that the gene is defective; we must also know how the affected gene actually causes the disease. Knowledge of the downstream biological cascade caused by the gene allows scientists to address the mechanistic malfunction at the appropriate step along the dysfunctional pathway.

The first gene therapy trial was reported in 1975 (Terheggen et al., 1975; Tamura and Toda, 2020), but it wasn’t until 2017 that the first gene therapy was approved by the FDA (U.S. Food and Drug Administration, 2017). Now, there are currently 25 FDA-approved gene therapeutics, spanning a variety of different conditions (U.S. Food and Drug Administration, 2022). With many more gene therapeutics in clinical trials, including some in Parkinson’s disease and Alzheimer’s disease, the field has definitely come a long way. While many disorders tend to be far too biologically complex for the current state of gene therapy to address, the tremendous scientific progress made thus far leaves us hopeful for what is to come.

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Written by Justin McMahon

Illustrated by Sumana Shrestha

Edited by Caitlin Goodpaster and Liza Chartampila

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References
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