Gene Therapy: Cutting Edge Neuroscience in Medicine

By Justin McMahon

Around 1 in 4 people will be affected by a mental illness at some point throughout their lives (World Health Organization, 2022), and unfortunately up to 60% of patients with psychiatric disorders are treatment resistant (Howes et al., 2022). While fewer people are resistant to treatments for neurological disorders such as epilepsy or dementia, there are few therapeutics available to effectively treat these conditions. With the total burden of both neurological and psychiatric disorders continuing to grow as the global population increases and ages (Feigin et al., 2019; GBD 2019 Mental Disorders Collaborators, 2022), scientists are hard at work to develop innovative therapeutics like gene therapy to address this need for more effective treatment options. In fact, at the time our Neuro Primer on gene therapy was published back in December of 2022, there were 25 FDA-approved gene therapeutics. Now, just over 8 months later, there are 32 (U.S. Food and Drug Administration, 2023)!

Gene therapy offers a new approach to treating diseases, and involves the delivery of a healthy copy of instructions to cells that are affected by a genetic condition. Scientists employ several different methods in order to effectively target the unhealthy cells with a gene therapeutic. Viruses, because of their natural ability to seek out and deliver biological materials to specific cells, have become one of the most common approaches to deliver gene therapeutics to humans. Here we unpack the challenges of developing gene therapeutics in medical neuroscience, along with important ethical and safety considerations for this next generation of treatment options.

Neuroscience challenges in gene therapy 

Even if a therapeutic is able to provide the necessary instructions to treat a disorder, a gene therapy is only as good as its ability to target the affected tissue and/or cell types. There are many ways to administer or inject a gene therapy, but the therapeutic must be able to pass the brain’s highly-selective blood brain barrier (BBB) in order to treat a brain condition. Therapeutics which target the eye (e.g., to treat degenerative blindness) or the peripheral nervous system (e.g., to treat spinal muscular atrophy) have been very successful (Daley, 2021; Ogbonmide et al., 2023), but this is partly due to the fact that these therapeutics do not need to cross into the brain to have their effect. The BBB poses a unique challenge to the use of viruses for treatments that target the brain, as its primary function is to regulate the passage of particles into or or out of the brain, with the goal of blocking out potentially harmful ones such as viruses. Despite it being beneficial for our brains to remain protected when the body encounters pathogens in our environment like the common cold, scientists needed a way to circumvent this obstacle in order to develop virus-based gene therapy treatments for brain conditions. Adeno-associated viruses (AAVs) have become the most common viral vector for gene therapeutics since they are both nonpathogenic and able to cross the BBB (Wang et al., 2019).

Once the gene therapy enters the brain, it is essential that it exclusively targets the dysfunctional cells. For example, imagine a person who suffers from a rare form of genetic epilepsy which causes them to experience severe seizures. Seizures are triggered by an overactivity of neurons in the brain – but not all neurons are involved (Anwar et al., 2020). This is important, because in the development of a gene therapy which aims to reduce the activity of some of the affected neurons in this hypothetical condition, scientists need to make sure that they are not reducing the activity of all neurons in the brain: this would be a fatal overcorrection. Typically in gene therapeutics, the goal is to restore the patient’s biology to a healthy functioning level (i.e., making precise adjustments to ensure that changes are not overly drastic and capable of causing problems in the opposite direction).

To address these challenges, scientists have come up with multiple ways to adjust AAVs in order to target different cells. One common approach is modifying the capsid, or protein shell of a virus (Foust et al., 2009, Chan et al., 2017, Goertsen et al., 2021). Thanks to COVID-19, we are all familiar with the spiky appearance of the coronavirus capsid. AAV capsids also have a signature look to them, icosahedral in shape like a 20-sided die. Scientists are able to make minor adjustments to this protein shell so that a specific virus can recognize the outer proteins of a particular cell. Once this recognition step has occurred, so begins the process of gene delivery.

Ethics and safety

Once a gene therapy seems to hold enough promise to be an effective treatment option, scientists must consider how to bring the therapeutic from the lab to the clinic: a process which is tightly regulated. In the U.S., all clinical trials are overseen by the Food and Drug Administration, which involves the evaluation of the safety and the effectiveness of a new treatment. Before a treatment proceeds into clinical trials for humans, research and development teams rigorously test the safety and efficacy in animals (commonly mice and monkeys).

Clinical trials regulated by the FDA can take eight years or more to complete before a decision is made on whether or not to approve the treatment for the public (American Society of Gene + Cell Therapy, 2021). During this time, researchers assess the following aspects of treatment: safety, dosage, the best way to administer it, how well the treatment actually treats the disease (i.e., efficacy), and if it is better than the current standard treatment.

Gene therapeutics of course have many ethical considerations. Some of the most prominent ethical debates have involved the types of disorders being treated, the editing of embryos, and the hefty price tag of receiving this kind of treatment. In 2018, news broke that the first gene-edited embryos were created: Chinese researcher, He Jiankui, edited a gene to disable the pathway used by HIV to infect cells (Cyranoski and Ledford, 2018). People across the globe were quick to express their concern, expressing that these experiments have gone too far – and that gene therapeutics were getting too close to practicing eugenics (arranging human reproduction to obtain desired traits). Jiankui was subsequently banned from his institution and sentenced to 3 years in jail (Normile, 2019). 

What’s next?

Given the already immense challenge of trying to target the correct cell type for a well-understood disease, the current state of gene therapy has a ways to go before holding promise for treating complex disorders which result from many different genetic mutations – such as autism spectrum disorder, schizophrenia, or bipolar disorder. However, there are hopeful clinical results for gene therapeutics aiming to treat neuropsychiatric disorders that have less complex genetic causes, including: Huntington’s disease, some forms of Parkinson’s disease, and some forms of Alzheimer’s disease (Haggerty et al., 2020; University of California San Diego, 2021). For more genetically complex conditions such as autism spectrum disorder, think about the disorder as being composed of many biological pathways. These pathways lead to different symptoms that together make up the condition. As scientists begin to uncover the individual biological pathways which contribute to the most severe symptoms there is hope that one or more of them will serve as a promising target for gene therapy to make the disorder more manageable (Sestan & State, 2018).

In addition to questioning the efficacy of next generation therapeutics, it is crucial to continue having discussions about the ethics and safety of new technologies in medicine. What makes one genetic outcome okay to adjust versus another? Who will be able to afford the high cost of these therapeutics? If the use of gene therapeutics becomes widespread, will society view untreated individuals differently? The future of medical neuroscience is an exciting one, but not one that should go without critical evaluation.

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Written by Justin McMahon

Illustrated by Yang-Sun Hwang

Edited by Zoë Dobler, Johanna Popp, and Daniel Janko

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References

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