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 Alpha-synuclein

  • 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)
  • In the several years since its discovery, α-synuclein has been the focus of intensive efforts by basic Parkinson's disease researchers working to definitively characterize the protein's role in Parkinson's and its potential as a target for neuroprotective therapies

SNCA Gene and SLS-004

  • At present, there is no effective treatment to prevent PD or halt its progression
  • The SNCA gene, which encodes alpha-synuclein expression, has been implicated as a highly significant risk factor for PD
  • Accumulating evidence suggests that elevated levels of wild-type alpha-synuclein are causative in the pathogenesis of PD
  • The role of SNCA overexpression in PD pathogenesis and the need to maintain normal physiological levels of alpha-synuclein protein emphasize the so-far unmet need to develop new therapeutic strategies, such as SLS-004, targeting the regulatory mechanisms of SNCA expression

SLS-004: Targeted Epigenome-Editing

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.