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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Gene silencing halts neuron degeneration in ALS mice

Scientists at the University of California San Diego School of Medicine have developed a technique to deliver gene-silencing vector to adult amyotrophic lateral sclerosis (ALS) mice. Delivery of this vector prior to disease onset resulted in long-term suppression of the disease in mice.

ALS is a neurodegenerative disease that affects motor neurons in the brain and spinal cord. The incidence of ALS is estimated to be 2 cases in 100,000 persons in the United States and in Europe, or up to about 30,000 new cases of ALS per year. It is estimated that 10% of all cases are thought to be inherited as a dominant trait, or otherwise known as Familial ALS (FALS.)

Approximately 15 to 20 percent of FALS cases are caused by mutations in the gene that produces the copper zinc superoxide dismutase 1 (SOD1) enzyme, which leads to a progressive degeneration of motor neurons affecting movement and muscle control. Despite decades of intense research, treatment options remain limited for the majority of ALS patients.

Viral-mediated shRNA delivery for gene silencing represents a promising approach to treat neurodegenerative disorders. Although this technique has been tried before for ALS, where the shRNA was injected into the cerebrospinal fluid of ALS mice, disease progression had initially delayed but the disease continued and the mice had died.

In the present study published in Nature Medicine, Prof. Martin Marsala and team at UC San Diego School of Medicine developed an alternate technique, where shRNA targeting the SOD1 gene was packaged into an AAV vector and injected into the subpia (below the pia matter, the delicate innermost membrane enveloping the brain and spinal cord) of adult mice with SOD1 gene mutation either just before disease onset or when the animals had begun showing symptoms.

Results showed that in adult mice already displaying ALS-like symptoms, the injection effectively blocked further disease progression and degeneration of motor neurons. The affected mice lived without any negative side effects during the entire length of the study.

The team also tested the approach in adult pigs using a newly designed device and noticed that the procedure could deliver shRNA homogeneously and reliably throughout the cervical spinal cord and brain motor centers.

The team will now test the approach in larger animal model to determine the optimal, safe dosage of treatment vector. If successful, the approach will be a critical step in advancing this treatment approach toward clinical testing.

Prof. Marsala commented: “At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS. In addition, effective spinal cord delivery of AAV9 vector in adult animals suggests that the use of this new delivery method will likely be effective in treatment of other hereditary forms of ALS or other spinal neurodegenerative disorders that require spinal parenchymal delivery of therapeutic gene(s) or mutated-gene silencing machinery, such as in C9orf72 gene mutation-linked ALS or in some forms of lysosomal storage disease.”

Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS. Bravo-Hernandez M et al., Nature Medicine. DOI

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