Gene Therapy SLS-004 Prevents Neurodegeneration In Mouse Model

Investigational epigenetic therapy lowers alpha-synuclein levels

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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SLS-004, Seelos Therapeutics‘ investigational gene therapy for Parkinson’s disease, lowered alpha-synuclein levels and prevented the degeneration of dopamine-producing, or dopaminergic, neurons in a mouse model of the disease, the company announced.

A hallmark of the neurodegenerative disease, the loss of dopaminergic neurons in a brain region called the substantia nigra pars compacta (SNpc) is known to drive the cardinal symptoms of Parkinson’s.

“These data suggest that SLS-004 may have substantial potential for a disease-modifying gene therapy in Parkinson’s disease,” Raj Mehra, PhD, chairman and CEO of Seelos, said in a company press release.

In Parkinson’s, the brain-abundant alpha-synuclein protein forms toxic clumps inside neurons, disrupting their function and ultimately leading to their death. Notably, mutations in SNCA, the gene that gives instructions for making alpha-synuclein, are associated with early-onset forms of the neurodegenerative disease.

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According to Seelos, patients with impaired regulation of SNCA can have alpha-synuclein levels as high as 200%, and promoting a reduction of 25%–50% is expected to be sufficient to restore normal levels.

As such, reducing the activity of the SNCA gene, subsequently the production of alpha-synuclein, may be one way to prevent the excessive buildup of alpha-synuclein in Parkinson’s.

Originally developed by researchers at Duke University, SLS-004 aims to lower SNCA’s activity through an epigenetic modification. Epigenetic modifications refer to the addition of chemical marks to DNA by a group of specialized enzymes that influence genes’ activities without altering their underlying DNA sequence.

In this case, SLS-004 delivers the DNA methyltransferase 3A enzyme to cells. The enzyme works to specifically “turn off” SNCA by adding a methyl group, a type of epigenetic marker, to a certain part of the gene.

The enzyme is directed to the right place using components of CRISPR-dCas9, a system adapted from the natural defense mechanisms of bacteria to guide epigenetic modifications to particular DNA sequences.

Both these components and the enzyme are delivered to cells through a modified and harmless version of a lentivirus.

Early preclinical studies demonstrated SLS-004 reduced alpha-synuclein levels by about 30% in lab-grown neurons from a Parkinson’s patient. It also improved neuronal survival and reduced other Parkinson’s-associated cellular changes.

Last year, Seelos released data demonstrating the treatment, when injected directly into the SNpc of healthy mice, reduced alpha-synuclein levels.

Over the summer, the company also announced that SLS-004, with a modification to its viral carrier, was also able to lower alpha-synuclein production in lab-grown cholinergic neurons. These are the cells primarily affected in dementia with Lewy bodies, a related condition also marked by alpha-synuclein buildup.

Gene therapy tested in mice model

Newly announced data concern experiments in which researchers tested the gene therapy in a mouse model of Parkinson’s.

To generate the model, the team injected a modified virus containing a gene with the instructions to produce a clumping-prone alpha-synuclein protein, directly in the SNpc of the mice on both sides, or hemispheres, of the brain.

In this model, mice produced high levels of this abnormal alpha-synuclein, leading to degeneration of dopaminergic neurons. Dopaminergic neurons can be identified by the presence of a protein called tyrosine hydroxylase, or TH.

These mice were also injected with a single dose of SLS-004 directly into the SNpc in one hemisphere and a lentivirus without the treatment components (sham injection) in the SNpc of the other hemisphere.

Results showed that SLS-004-treated SNpc had a substantial increase in tyrosine hydroxylase (TH)-positive dopaminergic neurons, compared with the sham-injected counterpart. TH is a key enzyme in dopamine production.

“Increasing the recovery of [TH-positive] dopaminergic neurons after a single administration of SLS-004 is a significant achievement, and this [animal] study validates and extends our prior findings,” Mehra said.

The company now plans to continue developing SLS-004 for Parkinson’s. Seelos received a grant from the Michael J. Fox Foundation for Parkinson’s Research earlier this year to advance the therapy’s research program.

Seelos has another therapeutic candidate for Parkinson’s in development. Called SLS-007, the treatment also aims to reduce alpha-synuclein buildup, but through a distinct mechanism.

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