SOL-257, an experimental one-time gene therapy, was well tolerated and significantly improved disease outcomes in two distinct mouse models of amyotrophic lateral sclerosis (ALS).

Developed by Sola Biosciences, SOL-257 is designed to clear the toxic TDP-43 protein that accumulates and forms clumps in ALS nerve cells, contributing to disease progression. The therapy significantly extended survival in one model, and improved muscle strength and motor function in the other.

Data from the preclinical studies were presented this week at Neuroscience 2023 in Washington, D.C.

“Our findings underscore SOL-257 as a highly promising translational therapy for ALS,” Akinori Hishiya, PhD, chief scientific officer at Sola, said in a company press release. “Demonstrating efficacy in two distinct genetic mouse models of ALS supports our confidence that by targeting misfolded TDP-43, SOL-257 holds the potential to treat a vast majority of ALS patients.”

Abnormally folded TDP-43 is a common feature in both sporadic and familial types of ALS. It’s observed in about 97% of all ALS cases.

TDP-43 is normally found in the nucleus, where it regulates the first step of protein production from a gene. In ALS, the protein can take an abnormal shape, one more prone to accumulate in the cytoplasm and form toxic clumps, leading to cell damage and death.

What does SOL-257 do?

SOL-257 is designed to target the misfolded TDP-43 and either promote its proper folding or facilitate its degradation, which ishould reduce nerve cell damage and slow disease progression.

It was developed with Sola’s JUMP70 technology platform, which promotes the production of JUMP70, a protein that connects the misfolded proteins to the patient’s own HSP70 chaperones. Chaperones are proteins that help other proteins fold correctly or direct misfolded ones to be degraded.

The company is developing JUMP70-based therapies for a number of conditions marked by abnormal protein folding and aggregation, including Huntington’s, Alzheimer’s, and Parkinson’s diseases, as well as cystic fibrosis.

The therapies use a modified and harmless adeno-associated virus (AAV) to deliver the JUMP70 gene to cells. The resulting two-part protein is specific to both HSP70 and to each disease-causing misfolded protein.

With SOL-257, the protein is designed to bring together HSP70 and the misfolded TDP-43 proteins, while leaving functional TDP-43 alone to do its job.

In an earlier study, researchers showed SOL-257 significantly extended the survival of mice genetically modified to allow the controlled production of misfolded TDP-43.

SOL-257 effects on two mouse models of ALS

Sola showed additional data from that model along with another mouse model in which animals carried mutations in the C9ORF72 gene, whose defects are the most common genetic cause of ALS. These mutations are thought to trigger TDP-43’s movement out of the nucleus, where it misfolds.

“I’m thrilled to announce SOL-257, a breakthrough gene therapy poised to tackle ALS by targeting TDP-43 pathology. Our compelling preclinical data highlights a significant step toward harnessing the body’s cellular defenses,” said Keizo Koya, PhD, Sola’s CEO. “Committed to excellence, we are advancing this promising therapy, striving to bring hope to the ALS community.”

In the first model, researchers showed that pretreatment with SOL-257 before abnormal TDP-43 production was induced suppressed the toxic clumps and significantly prolonged survival. All untreated animals died in the first eight weeks, but some treated ones lived for up to 17 weeks.

The intracerebroventricular injection, that is, one directly into the brain, that was used to deliver the viral vector carrying JUMP70 was well tolerated in mice, the researchers said.

To develop the C9ORF72 mouse model, mice were injected into the brain with a C9ORF72 gene carrying 149 repetitions of six specific DNA building blocks (GGGGCC) in its genetic sequence. In these animals, toxic TDP-43 clumps were found to build up over time and cause death.

The animals were treated with SOL-257 after letting the disease progress for three months. At this more advanced stage, the gene therapy also significantly reduced toxic TDP-43 clumps in the brain.

Mice were subjected to an open-field test, which uses the distance walked over a given time as a proxy to assess hyperactivity, a sign of neurodegeneration. Hyperactivity steadily declined between six and nine months after the SOL-257 injection, but increased in untreated mice.

Mice also underwent a wire hang test, which measures how long it takes to fall off a wire, to assess motor function and muscle strength. At nine months, untreated mice fell off significantly faster than SOL-257-treated mice.

The data supports the continued development of SOL-257 to treat ALS.

“The robust … proof-of-concept data makes me excited to complete the preclinical studies necessary to take SOL-257 into ALS clinical trials,” Gerry Cox, chief medical officer at Sola, said in an email to ALS News Today. “The unmet medical need in ALS remains high, despite the current therapeutic landscape, and the prospect of a broadly applicable, one-time therapy brings new hope to the ALS community.”