Seelos therapeutics announced positive data in a rodent model of its CRISPR-dCAS9 gene therapy for Parkinson’s disease. This appears to be a second example of how CRISPR genes are manipulated in the body, as opposed to cell cultures.
June 26th Intellia therapeutics and Regeneron Pharma announced Phase I human data from its in vivo gene editing candidate NTLA-2001 for transthyretin (ATTR) amyloidosis. To date, CRISPR-Cas9 gene editing is typically performed on cells in culture and then re-infused into a patient. The approaches reported by Seelos, Intellia, and Regeneron suggest injecting gene therapy directly into the body.
Seelos indicated that her SLS-004 demonstrated downregulation of SNCA mRNA and protein expression in a rodent model of Parkinson’s disease. A single dose of gene therapy resulted in a 27% reduction in SNCA mRNA and a 40% decrease in SNCA protein expression.
SLS-004 uses an all-in-one lentiviral vector containing dCas9 DNA methyltransferase 3A (DNMT3A) to enrich DNA methylation with CpGs islands in the SNCA intron 1 region.
The SNCA gene has been linked to a high genetic risk for Parkinson’s disease. There is also evidence that elevated alpha-synuclein levels are the cause of Parkinson’s disease. Patients whose SNCA regulation is disturbed have an expression of the alpha-synuclein protein of up to 200%. It is believed that a 25-50% decrease in SNCA mRNA and protein expression is sufficient to restore normal physiological levels of SNCA.
“We are very encouraged by these preliminary results, which demonstrate down-regulation of SNCA mRNA and SNCA protein expression in this in vivo model,” said Raj Mehra, Chairman and Chief Executive Officer of Seelos. “The overexpression of alpha-synuclein has been implicated as a highly significant risk factor for Parkinson’s disease, and the accumulation of this protein is a pathological indicator of synucleinopathies for additional diseases such as dementia with Lewy bodies and multiple system atrophy.”
The study looked at 24 adult C57 / B6 mice. Each received stereotactic infusions of viral vectors into the substantia nigra of the left hemisphere. The right hemispheres of the mouse brains received no injections and served as internal controls and baseline values for each rodent. The substantia nigra is believed to be the key region of the brain associated with Parkinson’s disease. It is a group of nerve cells that produce dopamine. Its degeneration is the leading cause of motor symptoms in the disease.
Different cohorts carried different repressors. One carried KRAB-MeCp2 and gRNA targeted the mouse SNCA intron 1. This cohort showed a consistent and average trend of 27% reduction in mouse SNCA mRNA and an average reduction of 40% in SNCA protein expression. Another cohort used DNMT3A as an effector and showed “a more subtle effect on both SNCA mRNA and protein levels (averaging almost 10% and 20% reductions, respectively”).
“The effect of the SNCA down-regulation achieved with our innovative CRISPR-dCas9 platform technology in this in vivo animal study is very promising and we plan to enhance the safety and effectiveness of our lentivirus-based epigenome editing approach in a comprehensive to further validate the preclinical study under our Sponsored Research Agreement with Seelos, with the aim of reversing the Parkinson’s disease-related pathology, ”said Boris Kantor, Associate Research Professor at Duke University School of Medicine.
Seelos focuses on therapies for diseases of the central nervous system and rare diseases. It has several clinical benefits in late-stage acute suicidal ideation and behavior (ASIB) in major depression (MDD) or post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), Sanfilippo syndrome, Parkinson’s disease, and other psychiatric and movement disorders, and rare Diseases.
On July 6th, the company dosed the first patient in Part 2 of his proof-of-concept study of SLS-002 (intranasal racemic ketamine) for acute suicidal ideation and behavior (ASIB) in major depression (MDD).
“The goal of developing SLS-002 in the treatment of suicidal patients is to radically change the current standard of care,” said Mehra. “SLS-002’s potential for rapid onset of action, as suggested in Part 1 of our study, aims to show benefit as quickly as overnight. As a result, patients could possibly be discharged earlier and treated on an outpatient basis in the future. “