SfN18: The potential of gene therapy in neurological disorders

Written by Sharon Salt, Editor

Promising findings from preclinical animal studies presented at SfN Neuroscience (3–7 November, San Diego, CA, USA) show the potential of gene therapy in slowing down disease progression, and improving symptoms, in neurological disorders such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD).
Although gene therapy is a promising treatment option for a limited number of conditions, the technique is still experimental for most diseases, with ongoing research to ensure they will be safe and effective in human patients.

New technique allows gene therapy to be delivered to the spinal cord in mice

A new technique for gene therapy can permeate the entire spinal cord and parts of the brain in a mouse model of ALS, according to researchers. To treat a disease like ALS with gene therapy, scientists hypothesize that it is necessary to repress the activity of the mutated SOD1 gene in cells throughout the entire CNS. However, current techniques are not very effective at delivering such silencing vectors through the spinal cord in adult animals.

M Bravo Hernandez (University of California San Diego, CA, USA) and colleagues developed a new technique for gene therapy delivery, in which a virus carrying a SOD1-silencing vector is injected underneath the thin membrane surrounding the spinal cord. This ‘subpial’ gene-delivery technique has been reported to be highly effective in delivering the vector to the entire length of the spinal cord, as well as brain cells that control voluntary motor function in adult mice, rats, pigs and non-human primates.

In a mouse model of ALS, subpial silencing vector therapy resulted in significant therapeutic benefits: mice who received the treatment developed ALS about 70 days later.

“These data convincingly demonstrate that subpial injection is an effective way to deliver gene therapy throughout the entire spinal cord. We had success using this treatment strategy in a mouse model of ALS caused by SOD1 gene mutation, but one could target any inherited disease that affects the spinal cord by delivering the treatment using this technology,” concluded Hernandez. 

Gene therapy extends life and improves motor function in a mouse model of ALS

In a second study presented at SfN Neuroscience, researchers reveal that suppressing the activity of SOD1 improves symptoms and survival rates in a mouse model of inherited ALS.

In this research, a gene suppression therapy, AVXS-301, was reported to effectively silence SOD1 in neurons and astrocytes. When injected into the spinal canal, the treatment reduced mutant SOD1 protein in neurons and astrocytes, extended survival, and improved motor function. Additionally, studies in non-human primates also demonstrated that AVXS-301 was safe and effective at reducing mutant SOD1 protein throughout the spinal cord.

Gretchen Thomsen (Avexis, CA, USA), lead author of the study, concluded: “Our preclinical data indicates that our gene therapy is effective at reducing SOD1 not only in motor neurons, but also other cell types, such as astrocytes, an abundant cell type in the brain and spinal cord that has been implicated in ALS disease progression.”

“With these promising findings regarding safety and efficacy, we hope to move closer to clinical trials in human patients.”

Gene therapy slows the progression of neuronal loss in mouse model of PD

In a mouse model of PD, gene therapy has been described to clear misfolded protein, promote neuron survival and minimize disease progression rates.

Researchers have developed a gene therapy to increase the activity of glucocerebrosidase, a lysosomal enzyme encoded by the GBA1 gene. This treatment was highly efficient in inducing almost complete clearance of aggregated α-synuclein in the substantia nigra. Additionally, mice treated with the gene therapy lost significantly fewer neurons than the control mice.

A similar approach will soon be implemented in non-human primates to collect all relevant preclinical information before moving on to clinical trials with human patients.

“Currently available therapeutic options for patients suffering from PD can alleviate the main clinical symptoms, but they do not slow down the course of the disease. Treatments like our gene therapy show the potential to meaningfully impact patients by slowing down, or even arresting, disease progression,” concluded lead author Jose Lanciego (Fima-University of Navarra, Pamplona, Spain).

The promise of gene therapy in Batten disease

Batten disease is a fatal, neurodegenerative disorder. Children born with this disease develop normally as infants but begin to show cognitive and motor symptoms at around 2–5 years of age. The disease is characterized by seizures, progressive dementia, and loss of visual and motor functions, ultimately leading to death in the teenage years.

One genetic cause of Batten disease is mutations in the CLN6 gene that result in the absence or reduced abundance of CLN6 protein. The CLN6 protein is involved in clearing waste from the cells; when it does not function properly, the waste accumulates over time and ultimately interferes with cell function. Neurons and other cells in the brain and spinal cord seem to be particularly sensitive to the accumulation of waste, which often kills the cells and leads to the neurological symptoms.

In a collaborative effort, researchers injected an inert virus that carries a healthy copy of the CLN6 gene into the cerebrospinal fluid of mice. These mice carry a natural mutation in CLN6 and display characteristics of Batten disease similar to those found in human patients.

The treatment safely abolished the accumulation of cellular waste, ameliorated symptoms and drastically improved the survival of the animals. The scientists also injected the gene therapy into non-human primates and found that it was safe and well-tolerated.

“Our promising data and extensive safety studies have laid the groundwork for the initiation of a Phase I/II clinical trial in human patients that is currently ongoing at Nationwide Children’s Hospital in Columbus, Ohio (USA),” concluded lead author Shibi Likhite (Nationwide Children’s Hospital).

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  1. Bravo Hernandez M, Takadoro T, Platoshyn O et al. A potent treatment effect after spinal subpial adeno-associated virus (AAV9) shRNA-SOD1 delivery in adults ALS SOD1G37R Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 9677).
  2. Thomsen GM, Likhite SB, Corcoran S et al. Intrathecal AAV9-SOD1-shRNA administration for amyotrophic lateral sclerosis. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 13363).
  3. Lanciego JL, Rico AJ, Dopeso-Reyes IG et al. Glucocerebrosidase gene therapy induces alpha-synuclein clearance and stops disease progression. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 1921).
  4. Likhite SB, Cain JT, White KA et al. From bench to bedside: gene therapy for Batten (CLN6) disease. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 14655).