I dislike publishing about CRISPR technology or about ALS mice models yet the results in this article, if replicated, are amazing. It means that for 5% of ALS patients, there is an hope that a future drug might extend their survival by more than 12 years!
Although CRISPR-based gene-editing technology has received unreasonable hype, it represents a promising approach to providing genetic therapies for inherited disorders, including amyotrophic lateral sclerosis.
Toxic gain-of-function superoxide dismutase 1 (SOD1) mutations are responsible for approximatively 20% of familial Amyotrophic Lateral Sclerosis cases. This means 5% of all ALS cases.
Current clinical strategies to treat SOD1-Amyotrophic Lateral Sclerosis are designed to lower SOD1 levels, notably throught the use of ASOs. On October 17, 2021, a presentation of the phase 3 VALOR study indicating that Biogen's Tofersen did not demonstrate statistical significance in the primary measure of disease progression.
On June 3, 2022, additional 12-month open label extension data was presented, demonstrating a some positive effect for participants who received Tofersen early in their disease.
In this new publication, authors from Biogen used an AAV-gene therapy to deliver CRISPR guide RNAs designed to disrupt the human SOD1 transgene in SOD1 mice (huSOD1). Those transgenic mice express the human SOD1 gene, not the murine gene, so their disease is closer to the human disease than in other SOD1 mice models.
This intrathecal injection into neonatal huSOD1 mice caused robust and sustained mutant huSOD1 protein reduction in the cortex and spinal cord, and restored motor function.
Neonatal treatment also reduced spinal motor neuron loss, denervation at neuromuscular junction and muscle atrophy, diminished axonal damage and preserved compound muscle action potential throughout the lifespan of treated mice. SOD1 treated mice achieved significant disease-free survival, extending lifespan by more than 110 days. 110 days for a mice that can live 2 years is equivalent to 12 years for humans!
Yet this is not realistic for human patients, as even if we can detect patients at risk at neonatal stage, most of them will not develop ALS, and furthermore reducing their SOD1 level means they will be susceptible to the very diseases that this therapy tries to attenuate.
Importantly, a one-time intrathecal or intravenous injection of this therapy, immediately before symptom onset, also extended lifespan by at least 170 days.
The authors' approach also uncovered key parameters that resulted in improved efficacy compared to similar approaches and can also serve to accelerate drug target validation.
One question I have is why these technologies are not used to convert the mutated SOD1 gene into the normal wild-type SOD1 gene. This is important because living with reduced levels of SOD1 puts the patient at risk for neurodegeneration!
Let's hope this will lead to a full drug development program at Biogen. Yet there will be internal competition with the team in charge of Torfersen.