Seelos Therapeutics Announces Data Demonstrating Statistically Significant Downregulation of mRNA and Reduction of Alpha Synuclein in an In Vitro Gene Therapy Study of SLS-004 Utilizing CRISPR-dCas9 in Dementia with Lewy Bodies
- Category: DNA RNA and Cells
- Published on Friday, 10 June 2022 10:34
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- A Single Dose of SLS-004 Produced 19% Downregulation of mRNA and ~40% Reduction of Alpha-Synuclein Compared to the Control Group
- These Results Support Advancing SLS-004 into Additional Preclinical Studies in Dementia with Lewy Bodies
NEW YORK, NY, USA I June 9, 2022 I Seelos Therapeutics, Inc. (Nasdaq: SEEL), a clinical-stage biopharmaceutical company focused on the development of therapies for central nervous system disorders and rare diseases, today announced data demonstrating a statistically significant (p<0.01) 19% downregulation of mRNA and a ~40% reduction of alpha synuclein (α-synuclein) in an in vitro study of SLS-004, its gene therapy program utilizing CRISPR-dCas9, in dementia with Lewy bodies (DLB).
DLB is characterized by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites. In DLB, the pathological changes are observed in the neocortex and limbic systems with a distinguishing feature of cholinergic dysfunction, which is different from other Lewy body disorders such as Parkinson's disease. Cholinergic neurons are differentially vulnerable in various neuropathologic entities that cause dementia, including DLB. Available evidence points to early and substantial degeneration of these neurons in DLB.
"This current in vitro study extends the existing CRISPR program for Parkinson's disease to DLB as both disorders are synucleinopathies although affecting different neurons in separate regions of the brain. Our team's observation of a meaningful efficacy with a new CRISPR technology focused on cholinergic neurons in striatum for DLB is exciting indeed, as it reinforces our earlier findings in a Parkinson's disease model," said Raj Mehra, Ph.D., Chairman and CEO of Seelos. "Results producing statistically significant reductions in mRNA and α-synuclein are clinically meaningful. We plan to advance into additional preclinical studies in DLB and Parkinson's and expect additional data in the second half of this year."
Preliminary Findings of In Vitro Study
The goal of this in vitro study was to extend the existing SNCA-targeted epigenome therapy system (SLS-004) by modifying the viral vector to target specific cholinergic neurons in the cortex that are afflicted in DLB and validate the specificity and efficacy in human-induced pluripotent stem cells (hiPSC) derived neuronal systems.
The parental line SNCA-Tri hiPSC-derived system for the proof-of-concept model was utilized for the current study. hiPSC were differentiated utilizing earlier protocols used in SLS-004. Multiple batches of each differentiated neuronal type were evaluated, and successful differentiation of each batch was established.
The preliminary findings showed that following two weeks of differentiation into cholinergic neurons, there was a statistically significant (p<0.01) 19% downregulation of mRNA and a ~40% reduction of α-synuclein protein compared to the no treatment/repressor groups.
Seelos plans to advance the study of SLS-004 in DLB in additional preclinical studies and disclose further developments of this new CRISPR-based therapeutic technology in the future.
In July 2021, Seelos released positive preclinical in vivo data with SLS-004 in downregulation of overexpressed α-synuclein in a Parkinson's disease model and plans to release additional data in the second half of 2022.
About Dementia with Lewy Bodies
Dementia with Lewy bodies (DLB) is one of the two types of dementia that has Lewy body inclusions as hallmarks of pathology, the other being Parkinson's disease dementia. DLB's initial symptoms of decreased mental functioning in patients often appear similar to the onset of Alzheimer's disease. However, unlike Alzheimer's, progression of DLB can cause various movement issues as well as visual and auditory hallucinations.
DLB a progressive neurodegenerative disorder in which cognition, behavioral symptoms, and Parkinsonian symptoms worsen over time, shortening life expectancy and often requiring nursing home placement. There are currently no treatments with evidence of disease-modifying effects in DLB. Current treatment options are primarily symptomatic and targeted toward specific disease manifestations, including cognitive or behavioral symptoms, disabling Parkinson's symptoms, sleep behavior disorder and other symptoms.
SLS-004 is a novel epigenome-editing approach to modulate expression of SNCA gene mediated by modification of DNA-methylation. SLS-004 utilizes an all-in-one lentiviral vector harboring dCas9-DNA methyltransferase 3A (DNMT3A) to enrich DNA-methylation within CpGs island at the SNCA intron 1 region. The system resulted in a precise and fine-tuned downregulation (30%) of SNCA overexpression in hiPSC-derived dopaminergic neurons from a PD patient with the triplication of the SNCA locus (SNCA-Tri). Most importantly, the reduction of SNCA expression mediated by the developed system was sufficient to ameliorate disease related cellular phenotypes. The in vitro studies achieved several key milestones including the establishment that DNA hypermethylation at SNCA intron 1 allows an effective and sufficient tight downregulation of SNCA expression levels and suggests the potential of this target sequence combined with the CRISPR-dCas9 technology as a novel epigenetic-based therapeutic approach for PD.
SOURCE: Seelos Therapeutics