- Potential therapy for Prader-Willi Syndrome (PWS)
- We have discovered the DNA sequence that is essential for a therapeutic approach to PWS in the PWS critical region (PWSCR), a region that encompasses RNA transcripts that are needed for normal development
- Completely novel technology that allows the fully activation of maternal transcripts within the PWS critical region (PWSCR)
Background and Unmet Need
Prader-Willi syndrome (PWS) is a genetic disorder that affects 1 in 10,000 to 30,000 people, being categorized as a very rare disease, and maps to chromosome 15. It is characterized by neonatal hypotonia, and later in development, hyperphagia and consequent obesity as well as obsessive – compulsive behaviors and temper tantrums. Through a normal process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In PWS, there is no normal copy of the paternal chromosome 15, so patients only have the silent copies inherited from the mother. PWS is a disorder of genomic imprinting , an epigenetic process by which the chromosome 15 that is inherited from the father has a set of genes that are transcriptionally active while the same set of genes on the chromosome 15 inherited from the mother are transcriptionally silenced. In PWS, there is no normal copy of the paternal chromosome 15, so patients only have the silent copies inherited from the mother. A cure for PWS remains an unmet need.
UConn researchers have discovered a component of the switch off mechanism of the maternal chromosome 15, a protein called ZNF274. The team has discovered that ZNF274 tethers a complex to the maternal PWSCR that silences RNA transcripts that are needed for normal development. Failure to inherit active paternal copies of these transcripts causes PWS. The team has identified the exact DNA sequence within the PWSCR that is recognized by ZNF274 and this will allow end users to design molecules that block the ZNF274/PWSCR interaction, activate the maternal PWSCR RNA transcripts as a therapeutic approach to PWS.
Stage of Development/Advantages:
- Technology for generating PWS-specific iPSC and their neuronal differentiation to study aspects of epigenetic regulation and the PWS disease mechanism has been developed
- CRISPR lentiviral vectors have been used to target ZNF274 and generate ZNF274 knock out clonal derivatives of the PWS iPSC lines
- CRISPR-mediated knock out of ZNF274 in neurons from PWS iPSCs re-activates expression of maternal transcripts
- Potential gene therapy for PWS
Langouet, M. et al., Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons. Human Molecular Genetics, 2018, Vol. 27, No. 3 505–515.
Number: US 2021/0171943 A1
Name: Amit Kumar
Phone: (860) 486-6938