Directed Acetylation of Cytidine in Cellular mRNA through Engineered snoRNA Adapters for the Treatment of Haploinsufficiencies

Summary: 

The National Cancer Institute (NCI) seeks research co-development partners and/or licensees for engineered chimeric snoRNA guides that recruit NAT10 to a specific target and cause directed acetylation of the target. They could be used to treat haploinsufficiency-associated disorders or diseases.

Description of Technology: 

Haploinsufficiency (HI) is the loss of one allele of a gene. The resultant loss in associated protein expression/function is insufficient for a normal phenotype and manifests in a myriad of diseases. Such diseases include: [1] congenital malformations (e.g., eye defects, cleft lip/palate, etc.), [2] neurodevelopmental disorders (e.g., autism spectrum disorders, epilepsy, schizophrenia, etc.) and [3] disorders of maintenance and self-renewal. This latter category includes cancer predisposition syndromes, obesity, maturity onset diabetes of the young, and autoimmune disorders. In total, over 300 known human haploinsufficiencies exist. However, no therapies exist which can target these HIs without unbalanced protein expression and deleterious side effects.

Scientists at the NCI engineered chimeric small nucleolar (snoRNA) guides that recruit the enzyme NAT10 to a target transcript. The NAT10 enzyme acetylates specific cytidines in RNA, including at the ac4C site, through association with these snoRNA guides. In mRNA, ac4C modulates the level of protein produced per mRNA template, manifesting in moderate increases in net protein levels. For HI-related disorders or diseases, moderate increases in protein production alleviate disease phenotypes without the potential side effects of more substantial over-expression and protein production. The inventors developed a proof-of-principle snoRNA guide that recruits NAT10 to the target transcript GAPDH mRNA. The snoRNA was delivered into HeLa cells through incorporation into a minigene vector. Recovery of GAPDH transcripts and mass spectrometry confirmed successful targeted acetylation in these cells. This invention of directed acetylation through engineered snoRNA adapters would be useful for the treatment of haploinsufficiencies where moderate protein expression can lead to alleviation of disease phenotype.

The NCI is looking for research co-development partners and/or licensees to help develop these engineered chimeric snoRNA guides into clinically relevant therapeutics for the treatment of a variety of haploinsufficiencies.

Potential Commercial Applications: 

Patient-specific, RNA-targeting therapy for haploinsufficiencies such as:

• Congenital malformations
• Neurodevelopmental disorders 
• Cancer
• Autoimmune Lymphoproliferative Syndrome (ALPS)
• Myelodysplastic Syndrome (MDS)

Competitive Advantages:

• Potentially fewer and less severe side-effects compared with current gene therapy technology
• More moderate changes of protein expression 
• Promotion of endogenous protein biosynthesis