And antisense oligonucleotide is used for targeting region where methylation site nt-290 of SMN2 promoter region is located

Abstract

The invention provides an antisense oligonucleotide targeting a region where a methylation site nt-290 of an SMN2 promoter region is located. The antisense oligonucleotide can be combined to a key methylation region of an SMN2 gene promoter region to promote the overall transcription level of an SMN2 gene and the expression level of SMN protein in spinal muscular atrophy patient cells, and can be used as a new treatment target in an SMN targeting treatment strategy.

Description

Technical field[0001]The present invention relates to the field of antisense oligonucleotides, and more particularly to antisense oligonucleotides that target the region of the methylation site NT-290 of the SMN2 promoter region NT-290.Background technique[0002]Spinal Muscular Atrophy (SMA) is a common-stained recessive hereditary neuromuscular disease, resulting in a variation of spinal cord angles and medullary motor neurons, with proximal limbs and torso, symmetric muscle weakness And muscle atrophy is characterized by the progress of the condition and multiple systems. The incidence of the disease is approximately 1 / 6000 to 1 / 10,000 in the survival newborn, ranging from the first place in the infant letters, of which respiratory failure is the most common cause. The clinical manifestation of SMA is large, and the maximum motion function obtained according to the patient's onset age and the maximum exercise function is classified. The homozygous deletion or composite hybrid mutat...

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Problems solved by technology

However, these drugs have the following disadvantages: (1) AVXS-101: high-priced therapeutic drug (approximately RMB 14 million). Limitations of unknown long-term safety

(2) Nusinersen and Evrysid / Risdiplam: Both are imported drugs from abroad, which have limitations such as very expensive treatment price (1 million / year), response rate of about 50%, and unknown long-term efficacy and safety

Moreover, the two drugs only regulate the alternative splicing of SMN2 at the lower overall transcription level of the SMN2 gene to increase the expression level of the full-length transcription version, thereby increasing the expression level of SMN protein, but cannot increase the total amount of the transcription level of the SMN2 gene

(3) Histone deacetylase inhibitors: HDACi can promote hyperacetylation of the SMN2 gene promoter region, enhance transcription, and increase SMN levels, but the effect of HDACi is broad-spectrum, and it can produce effect, does not specifically target the promoter region of the SMN2 gene, and ultimately did not achieve ideal therapeutic effects in clinical trials

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