Seelos Therapeutics has acquired the rights for a gene therapy program targeting the regulation of the SNCA gene, which provides instructions to make alpha-synuclein, a key player in the development of Parkinson’s disease.
The accumulation of abnormal (misfolded) alpha-synuclein protein can result in toxic aggregates that lead to the death of dopaminergic neurons. These toxic aggregates are the main component of Lewy bodies and Lewy neurites found in the brains of Parkinson’s patients.
“Aggregation of misfolded alpha-synuclein appears to be a key pathogenic mechanism leading to neuronal dysfunction and death. Inhibition of synuclein production, such as through SLS-004, is an attractive therapeutic target that may reduce aggregation and slow disease progression,” Robert A. Hauser, MD, director of Parkinson’s disease and movement disorders at the University of South Florida, said in a press release.
Methylation — the addition of specific chemical (methyl) groups that sit on top of a particular region within DNA — can regulate the activity of a gene mainly by “switching” it off. This strategy that regulates the activity of a gene without changing its DNA sequence is called an epigenetic approach.
SLS-004, developed by researchers at Duke University, uses a modified, harmless form of a virus, known as lentivirus, to deliver an enzyme called DNA methyltransferase 3A and promote the methylation of a particular region of the SCNA gene. This system is based on CRISPR-dCas9 gene editing technology and intends to fine-tune SNCA expression, thus lowering alpha-synuclein production.
“The down regulation of SNCA overexpression, through [a] one-shot epigenetic editing tool such as SLS-004, is a promising therapeutic approach, as it has shown reversal of the disease-related phenotypes preclinically,” said Tim Whitaker, head of R&D at Seelos Therapeutics.
In preclinical studies, delivery of SLS-004 to dopamine-producing neurons — those that are gradually lost in Parkinson’s — derived from stem cells from a Parkinson’s patient altered the expression of the SCNA gene and decreased levels of alpha-synuclein. Furthermore, the therapy protected against disease-related changes, including the production of harmful reactive oxygen species (ROS) and low cell viability.
“Under Seelos, we plan to move forward with this innovative CRISPR-dCas9-based development onto in vivo studies in [Parkinson’s disease] animal models,” said professor Ornit Chiba-Falek, a researcher at Duke University and co-inventor of SLS-004.
Boris Kantor, Ph.D., also a co-inventor of SLS-004, and colleagues are planning to develop “more efficient Cas9 variants, to further improve the accuracy and efficiency of the developed technology.”