Major facilitator superfamily domain-containing protein 8 mutant pre-mRNA splice site (MFSD8 mutant splice site)

The MFSD8 mutant pre-mRNA splice site is a unique therapeutic target identified in a patient with a rare form of Batten disease, specifically Neuronal Ceroid Lipofuscinosis 7 (CLN7). This target is created by a SINE-VNTR-Alu (SVA) retrotransposon insertion within intron 6 of the MFSD8 gene, which introduces a cryptic splice-acceptor site (Kim et al., 2019, NEJM). This mutation causes the spliceosome to incorrectly process the pre-mRNA, resulting in the inclusion of a pseudo-exon and a premature stop codon that prevents the synthesis of functional MFSD8 protein. MFSD8 is a lysosomal membrane protein thought to act as a transporter, and its absence leads to the accumulation of lysosomal storage material and progressive neurodegeneration (UniProt Q8NHS3). The target is addressed by Milasen, a bespoke antisense oligonucleotide (ASO) designed to bind specifically to the mutant splice site. By sterically hindering the splicing machinery at this cryptic site, the ASO restores the correct splicing pattern and allows for the production of full-length MFSD8 protein. This target is significant as the first example of a n-of-1 therapeutic approach where a drug was developed to target a mutation unique to a single patient.

Other names

MFSD8 cryptic splice siteCLN7 mutant splice siteMFSD8 intron 6 SVA insertionMFSD8 c.937+914_937+915insSVA

Antisense oligonucleotide-mediated steric blocking of a cryptic splice site to restore normal pre-mRNA splicing and protein expression (Kim et al., 2019).