#CureSMA2018 – Exicure’s SNA Formulation of Nusinersen Raises SMN Protein Levels with Lesser Toxicity, Mouse Study Reports

Exicure’s gene c prolongs survival, increases the amount of SMN proteins, and shows limited toxicity in a mouse model of the disease, study data show.

The investigational compound is a spherical nucleic acid (SNA) formulation of nusinersen, the active substance in Spinraza, made by Biogen and approved to treat all SMA types.

SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene, critical for the function and survival of the nerves that control muscles. But all patients maintain a copy of a gene called SMN2, that can give rise to a shorter version of the SMN protein.

Spinraza boosts the amount of the SMN protein by increasing the levels of full-length messenger RNA (mRNA) generated by the SMN2 gene.

Exicure and it collaborators at The Ohio State University Wexner Medical Center presented their preclinical results in a scientific poster titled, “Nusinersen in spherical nucleic acid (SNA) format improves efficacy both in vitro in SMA patient fibroblasts and in Δ7 SMA mice and reduces toxicity in mice”, at the 2018 Annual SMA Conference taking place in Dallas through June 17.

Using a mouse model of SMA, researchers observed that treatment with Exicure’s SNA formulation prolonged survival by four-fold: 115 days compared to 28 days in nusinersen-treated mice.

Compared to nusinersen, the formulation also doubled the amount of healthy full-length SMN2 mRNA and protein in fibroblasts — the main cells of connective tissue — from SMA patients. Compared to untreated mice, the SNA therapy also doubled the levels of normal SMN mRNA in the spinal cord, data showed.

Importantly, the highest dose tested in mice lessened nusinersen’s toxicity.

“Exicure’s spherical nucleic acid version of nusinersen demonstrates increased survival and decreased toxicity in the translationally-relevant SMA mouse model,” David Giljohann, PhD, CEO at Exicure, said in a press release. “We believe these results are important for developing improved treatments for patients with SMA.”

This positive data suggests that the company’s technology platform could lead to treatments for other neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s, Giljohann added.

Exicure and Ohio State decided to collaborate to further validate and characterize the pharmacology of the investigational SNA compound in mice in August 2017.

Studies in animal models are being conducted by Arthur Burghes, PhD, a Wexner professor focused on the molecular biology of SMA and other genetic neuromuscular disorders, including Duchenne muscular dystrophy.