FOCUS Gene Therapy RIGHT IDEA, WRONG TARGET? Gene Therapy For Parkinson's Disease BY MADELEINE POPOFSKY AND RISHA CHAKRABORTY ART BY JUNGBIN CHA 22 Yale Scientific Magazine December 2023 www.yalescientific.org
Gene Therapy FOCUS Why do treatments fail? Sometimes there is an issue with the treatment’s target. Other times, the translation from an animal model to humans presents too big of a gap. Over the history of research on gene therapy, such failures have brought scientists closer to success. The idea behind gene therapy is to treat genetic diseases at their source by altering a missing or faulty gene. For Parkinson’s disease—in which loss of dopamineproducing (dopaminergic) neurons leads to slowness of movement and other severe motor symptoms in late stages—this approach has shown promise, but success has, thus far, been out of reach. Past research on gene therapy had targeted a part of the basal ganglia—which is responsible for motor control—called the striatum. In mouse models, this was quite successful, and several papers were published on different genes targeting this area. One of these papers, published in 1994, was covered in the Yale Scientific Magazine by Gautam Mirchandani (Vol. 66 No. 2), who called it a promising study. The proposed therapy was designed to target the gene for tyrosine hydroxylase (TH), an enzyme that is critical for synthesizing dopamine in a Parkinson-like disorder. “Hopes are that such a treatment will soon be available for human benefit,” Mirchandani wrote. Yet, these techniques have all since failed. The problem, in many of these cases, was actually the target. While easy to target in a mouse, the basal ganglia in humans has enlarged dramatically over the course of evolution. Since the striatum forms such a large part of the basal ganglia’s structure, it was simply too large of a target. “It is very difficult to cover it by injecting a virus,” said Jim Surmeier, a professor of neuroscience at Northwestern University Feinberg School of Medicine. He is one of the many scientists taking up the task of turning the coal of past failures into the future diamonds that will let gene therapy shine. “We fail more often than we succeed,” Surmeier said. “What distinguishes really good researchers is the ability to learn from your failures.” A New Target? Surmeier’s research challenges prevailing theories regarding the function of dopaminergic neurons and their site of action in Parkinson’s disease. Previous researchers had assumed that loss of dopamine in the striatum was sufficient to cause the primary motor symptoms associated with Parkinson’s. However, Surmeier developed a new animal model for Parkinson’s that involved disrupting Complex 1, an important protein for energy generation, in the mitochondria of dopaminergic neurons. The difference in this model was that, unlike most animal models for Parkinson’s which cause rapid onset of the severe motor symptoms, this model more closely mimicked human Parkinson’s with its slow onset. Motor symptoms only became apparent several months after gene editing. This more realistic model led to both a new potential cause of Parkinson’s in humans and a better lens through which to study how brain circuits contribute to the disease. Using this model, Surmeier discovered something unexpected. “When there was clear loss of striatal dopamine release, the animals were not Parkinsonian, contrary to the prediction of the classical model,” Surmeier said. His new theory takes into account the structure of the basal ganglia. While the striatum is a large complex within this structure, there are other nuclei— clusters of neurons that perform a specific function—modulated by dopaminergic neurons. One of these, which sits between the basal ganglia and the rest of the brain, is the substantia nigra pars reticulata (SNr). While the traditional model of Parkinson’s focuses on almost solely treating the striatum, Surmeier proposed the SNr as a new target for gene therapy. “The basal ganglia are organized like a funnel, with the SNr at the mouth of the funnel. Targeting the mouth of the funnel is the best way to control the output of the basal ganglia,” Surmeier said. Now armed with a location, Surmeier needed a gene. In his study published in Nature in 2021, he targeted aromatic acid decarboxylase (AADC), a key enzyme that converts the precursor levodopa into its final form of dopamine. Levodopa is commonly used as a treatment for Parkinson’s. However, its effects wear off with time and more advanced forms of the disease since the dopaminergic neurons that are dying are the primary producers of AADC. Thus, over time, the brain begins to lack sufficient AADC to convert levodopa into dopamine. In this trial in mice, Surmeier was able to use gene therapy to give a new group of neurons the ability to express A A D C — t h o s e in the SNr—which relieved motor deficits in Parkinsonian mice. Throughout the process, Surmeier emphasized that one has to be willing to both challenge past assumptions and learn from past failures. When he first received the data from his new Parkinsonian model, Surmeier was skeptical enough to ask others to repeat similar experiments, again and again, when his results did not match preconceived notions. “In science, we never have truth in our hands,” Surmeir said. “It is always an approximation.” Yet Another Target? Surmeier’s work is only the tip of the iceberg when it comes to developing gene therapies for previously intractable diseases. His successful process of choosing just the right nucleus for targeting, and just the right enzyme to target for modification, is the result of not just personal failures, but also the failures, and successes, of many of his colleagues. One such colleague is Krzysztof Bankiewicz at the Ohio State College of Medicine. Bankiewicz has been interested in dopamine and Parkinson’s disease since the 1980s, when he joined one of the first clinical trials to restore normal dopamine levels in the brain to reverse Parkinsonian symptoms. The clinical trial intended to transplant cells that could produce dopamine into the www.yalescientific.org December 2023 Yale Scientific Magazine 23
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