About SLS-004 (gene therapy)
SLS-004 is a Gene Therapy Program Targeting the Regulation of the SNCA Gene, Which Encodes Alpha-synuclein (α-synuclein)
- All-in-one lentiviral vector, for targeted DNA-methylation editing within intron 1
- The system is based on CRISPR-dCas9 fused with the catalytic domain of DNA methyltransferase 3A (DNMT3A), an enzyme that is responsible for DNA methylation
- The system was delivered to dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) from a PD patient
- As a result, the expression of SNCA was modified and disease-related cellular-phenotypes characteristics of the neurons were reversed
About SNCA Gene and Alpha-synuclein
- The SNCA gene, which encodes alpha-synuclein expression, has been implicated as a highly significant risk factor for PD
- Alpha-synuclein (α-synuclein) is a protein whose function in the healthy brain is currently unknown
- α-synuclein is a protein which is of great interest to Parkinson's researchers because it is a major constituent of Lewy bodies and Lewy neurites, protein clumps that are the pathological hallmark of synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)
- The role of SNCA overexpression in PD pathogenesis and the need to maintain normal physiological levels of alpha-synuclein protein emphasize the unmet need to develop new therapeutic strategies, like SLS-004 targeting the regulatory mechanisms of SNCA expression
SLS-004 Preclinical Findings
- In vivo data has demonstrated down-regulation of SNCA mRNA and reduction of protein expression in a rodent model utilizing CRISPR-dCas9 gene therapy technology. A single dose of SLS-004 produced a therapeutically desirable 27% reduction in SNCA mRNA and a 40% reduction in SNCA protein expression.
- A single dose of SLS-004 produced a substantial increase in recovery of tyrosine hydroxylase-positive (TH+) dopaminergic neurons that are known to degenerate in patients with Parkinson's disease; TH+ degeneration has been attributed to the cardinal Parkinsonian symptoms of tremor, rigidity, bradykinesia and postural disturbances.
The findings above are from the abstract "SLS-004 - CRISPR-based epigenetic alpha-synuclein downregulation recovers loss of midbrain dopamine neurons in a humanized A53T Parkinson's rodent model" which was accepted and presented as poster on 2/22/2023 at the 11th Annual Alzheimer's & Parkinson's Drug Development Summit in San Francisco, CA.
In August 2022, Seelos received a grant from The Michael J. Fox Foundation for Parkinson's Research to advance preclinical research and development for the SLS-004 program.
SLS-004: Targeted Epigenome-Editing
Kantor B, et al. (2018) Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.08.019.