Seelos Therapeutics, Inc. announced in vivo data demonstrating that a single dose of SLS-004 downregulated the production of alpha-synuclein (a-synuclein). This reduction of a-synuclein by SLS-004 in an established a-synuclein overexpressing animal model of Parkinson's disease (PD) resulted in substantial increase and recovery of degeneration in tyrosine hydroxylase positive (TH+) dopaminergic neurons. TH+ dopaminergic neurons in the midbrain region, called substantia nigra pars compacta (SNpc), are known to degenerate in patients with PD.

This degeneration is attributed to lead to the cardinal Parkinsonian symptoms of tremor, rigidity, bradykinesia, and postural disturbances. These findings observed in an in vivo PD model validate and extend prior findings from in vitro data using SLS-004. SLS-004 demonstrated therapeutically desirable reduction in SNCA mRNA (a-synuclein messenger RNA) which led to reduced a-synuclein protein expression.

Preliminary Findings of In Vivo Study: The goal of this in vivo study was to validate and extend the findings in an established animal model of PD based on prior in vitro results that were described in human-induced pluripotent stem cells (hiPSC) derived neuronal system from well-characterized Parkinson's patients with triplication of the SNCA locus (SNCA-Tri hiPSC-derived system). The human A53T a-synuclein viral vector that expresses human A53T a-synuclein to model PD in animals was used in this study with the addition of human intron 1. The human A53T a-synuclein viral vector has been characterized in the mouse, rat and non-human primate models for its ability to: express human A53T a-synuclein, induce nigrostriatal degeneration, and model PD pathology when administered in the substantia nigra pars compacta (SNpc). The SNpc is an area in the brain that is known to degenerate in PD and is believed to be the causative factor for the cardinal signs of the disease such as tremor, rigidity, bradykinesia, and postural disturbances.

The administration of the disease inducing vector in the SNpc leads to increased production of a-synuclein protein that leads to nigrostriatal degeneration and thus reduces the number of TH+ midbrain dopaminergic neurons in the SNpc. In this study, the disease inducing vector was injected into the SNpc along with either the test article SLS-004 or control article in the other hemisphere and brain tissues were evaluated at the end of the study. The preliminary findings indicate that a single dose of SLS-004 administered in the SNpc of the test hemisphere in the brain produced a substantial increase in and recovery of degenerating TH+ dopaminergic neurons compared to the administration of the control vector in the SNpc of the other hemisphere.

The nigrostriatal degeneration of TH+ midbrain dopaminergic neurons in the SNpc is implicated in PD pathology and attributed to the cardinal signs of parkinsonian symptoms. In July 2021, Seelos announced positive in vivo data demonstrating down-regulation of SNCA mRNA and protein expression from a study of SLS-004 in an in vivo 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. Seelos plans to advance the study of SLS-004 in PD and in August 2022, Seelos was selected to receive a grant from The Michael J. Fox Foundation for Parkinson's Research to advance preclinical research and development for the SLS-004 program.

Also, In June 2022, Seelos released statistically significant data in an in vitro gene therapy study of SLS-004 utilizing CRISPR-dCas9 in dementia with Lewy bodies.