Epigenetic Editing Therapy SLS-004 lowers alpha-synuclein in mice

SLS-004, Seelos Therapeutics’ experimental epigenetic editing therapy for Parkinson’s disease, effectively reduced the production of alpha-synuclein – the protein that builds up in toxic clumps in Parkinson’s disease – in the brains of healthy mice.

Epigenetic modifications refer to the addition of chemical tags to DNA by a group of specialized enzymes that affect the activity of genes without altering the underlying DNA sequence.

In contrast to gene editing therapies, in which certain DNA segments are added, removed or changed, epigenetic editing enables medium to long-term regulation of the activity of a gene and thus the production of the resulting protein. This leaves the underlying genetic sequence intact.

“We are very encouraged by these preliminary results showing a downregulation of SNCA … in this in vivo model,” said Raj Mehra, PhD, Chairman and CEO of Seelos, in a press release.

The overproduction of alpha-synuclein has been implicated as a highly significant risk factor for Parkinson’s and the accumulation of this protein is [disease-related] Hallmarks of Parkinson’s and other synucleinopathies, said Mehra. Synucleinopathies are conditions associated with toxic alpha-synuclein clumps.

Ornit Chiba-Falek, PhD, co-inventor of SLS-004 at Duke University School of Medicine, said, “This pilot experiment in mice showed promising results with an effect on SNCA [alpha-synuclein] Reduction within the assumed therapeutic target window. “

“We are continuing preclinical studies to advance the evolution of epigenome editing targeting the SNCA into precision medicine for Parkinson’s disease,” added Chiba-Falek.

“We plan to further validate the safety and effectiveness of our lentivirus-based epigenome editing approach in a comprehensive preclinical study as part of our Sponsored Research Agreement with Seelos, with the aim of reversing Parkinson’s disease-related disease. ” [mechanisms]“, Said Boris Kantor, PhD, also co-inventor of SLS-004 at Duke.

Under this agreement, Seelos, which acquired the rights to SLS-004 in 2019, is sponsoring pre-clinical proof-of-concept studies at Duke to determine whether the therapy is safe and effective in preventing disease progression in a mouse model of Parkinson’s disease / or may delay.

It is expected that further preclinical models will be used in the future to further validate the potential of the therapy.

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Nerve cell loss in Parkinson’s disease is primarily triggered by the toxic build-up of alpha-synuclein clumps, a protein found in abundance in the brain that is believed to regulate the function and communication of nerve cells.

Patients with impaired regulation of the SNCA gene have up to 200% alpha-synuclein protein levels, and a reduction in SNCA messenger RNA (mRNA) and alpha-synuclein protein levels of 25-50% is expected to be sufficient, in order to restore normal levels of the protein, Seelos explained.

mRNA is the intermediate molecule derived from DNA that controls protein production.

SLS-004 uses a modified, harmless virus known as lentivirus to deliver CRISPR-dCas9 components for epigenetic processing and the enzyme DNA methyltransferase 3A (DNMT3A) to cells.

The original CRISPR-Cas9 system, discovered in bacteria as a defense mechanism, allows researchers to add, remove, or change specific sections of a DNA sequence. CRISPR-dCas9 is a modified version of the original system that, instead of modifying a particular genetic sequence, can regulate gene activity by directing epigenetic modifications to that sequence.

Guided by the CRISPR-dCas9 elements, DNMT3A “switches off” the SCNA gene, which provides instructions for the production of the alpha-synuclein protein by adding an epigenetic marker (called a methyl group) to a specific region of the gene.

By specifically switching off the activity of SCNA, SLS-004 is supposed to reduce the alpha-synuclein production and thereby limit or prevent the formation of toxic clumps in nerve cells. These lumps, also called Lewy bodies, damage the cells and eventually kill them off.

Previous preclinical studies showed that SLS-004 effectively suppressed the activity of SCNA and lowered alpha-synuclein levels in dopamine-producing neurons in a Parkinson’s patient. The therapy also improved neural survival and reduced disease-related changes. Dopamine-producing neurons are the cells that are progressively lost in Parkinson’s disease.

In the current study, Duke researchers treated healthy adult mice with either SLS-004 or a similar lentivirus- and CRISPR-dCas9-based approach that uses a potent gene activity repressor, KRAB-MeCp2, in place of DNMT3A.

Both treatments and empty, harmless lentiviruses (control condition) were injected directly into the substantia nigra on the left hemisphere of the animals, the right hemisphere being used as the internal control for each mouse. Susbtantia nigra, a brain region filled with dopamine-producing neurons and involved in motor control, is the key region affected by Parkinson’s neurodegeneration.

The results showed that treatment with SLS-004 resulted in an average reduction in SNCA mRNA levels of 10% and alpha-synuclein levels of 20% in the left substantia nigra compared to the untreated side.

Greater effects were observed with the KRAB-MeCp2 approach (a repressor bound to the CRISPR-dCas9 elements), as it resulted in an average decrease in SNCA mRNA levels of 27% and a decrease in alpha-synuclein 40% led. This was consistent with previous results in human cells, where the use of DNMT3A resulted in a 35 percent reduction in SNCA mRNA compared to a 55 percent decrease with KRAB-MeCp2.

The control condition showed no major differences in SNCA mRNA and protein levels between the injected and uninjected substantia nigra.

The animal showed no abnormalities within 10 days of the single injection. Researchers are currently performing a full analysis of all uninjected (control) brain structures and will repeat the experiment on additional mice while confirming the specificity of the injection site.

Seelos is also testing SLS-007, another Parkinson’s therapy candidate that aims to reduce alpha-synuclein aggregation.

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