Gene Therapy Around the Corner for Amyotrophic Lateral Sclerosis

For the first time, researchers used CRISPR-Cas9 gene editing technology in mice models to inhibit a gene that causes amyotrophic lateral sclerosis (ALS), according to a study published by Science Advances. This approach increased the lifespan of mice by 25% and may provide benefits to humans with ALS, according to the study.

Notably, the experimental gene therapy slowed the onset of muscle wasting associated with ALS, which can progress and become fatal. Although the genetic causes of ALS are not always known, all patients experience premature death of motor neurons and eventual loss of muscle control.

“Being able to rescue motor neurons and motor neuron control over muscle function, especially the diaphragm, is critically important to being able to not only save patients, but also maintain their quality of life,” said senior author David Schaffer, FRCP, FRCPsych.

In the study, mice were engineered to express a mutated gene that causes 20% of inherited cases of ALS. The authors used a virus that selectively seeks out motor neurons in the spinal cord to deliver a gene that encodes the Cas9 protein into the nucleus.

When the virus reached the nucleus, the Cas9 protein disabled the ALS-causing gene, according to the study. Specifically, Cas9 was engineered to cut out the mutated SOD1 gene.

The authors found that the gene therapy delayed the onset of ALS by nearly 5 weeks. Mice treated with gene therapy also lived a month longer than the typical 4-month life of a mouse with ALS, according to the study.

At death, surviving motor neurons in the mice were those that contained the Cas9 protein. This finding suggests that the protein may have protected motor neurons from death.

“The treatment did not make the ALS mice normal and it is not yet a cure,” Dr Schaffer said. “But based upon what I think is a really strong proof of concept, CRISPR-Cas9 could be a therapeutic molecule for ALS. When we do additional optimization of the delivery to get CRISPR-Cas9 into an even higher percentage of cells, we think we are going to see even better increases in lifespan.”

A significant challenge to developing a gene therapy that can cure ALS is knocking out the mutation in brain and spinal cord cells that support motor neurons, according to the study.

The authors are now developing a highly modified adeno-associated virus (AAV) that can deliver Cas9 to astrocytes and oligodendrocytes, which may affect neighboring cells.

“I tend to be really cautious, but in this case, I would be quite optimistic that if we are able to eliminate SOD1 within not just the neurons but also the astrocytes and supporting glia, I think we are going to see really long extensions of lifespan,” Dr Schaffer said.

The team is also developing a self-destruct switch for Cas9 so that once it deletes SOD1, the protein does not alter other genes, according to the study.

“We have engineered new AAV vehicles that are capable of high-efficiency delivery to a number of cell and tissue targets in the body, and when CRISPR-Cas9 came along, we viewed it as a wonderful opportunity to put together this incredibly powerful cargo with the ability to carry that cargo to a number of cells and disease targets in vivo,” he said.