US 2026/0306671 A1 · TRANSCRIPTION FACTOR 4 GENE EDITING SYSTEM

Abstract

Pitt-Hopkins Syndrome (PTHS) is a disorder characterized by severe intellectual disability and tendency for epilepsy. There is currently no treatment for PTHS. PTHS is caused by de novo mutations in Transcription Factor 4 (TCF4). No familial cases have been reported and all patients, except for two, have a unique mutation; many of which generate haploinsufficiency. Haploinsufficiency occurs in individual with one mutant allele, and the cell thus fails to meet the dosage of functional protein required for cellular function. Disclosed herein are gene editing systems that can enhance in vivo TCF4 expression.

Claims22

Dependent claims

A gene editing system comprising:

(i) a first nucleotide molecule encoding a catalytically inactive Cas9 (dCas9) protein fused to a miniaturized VP64-p65-Rta (mini VPR) transcriptional activator and further encoding an MS2-P65-HSF1 (MPH) transcriptional activation complex;
and
(ii) a second nucleotide molecule encoding at least one small guide RNA (sgRNA) comprising a scaffold region and a spacer region, wherein the scaffold region comprises MS2 stem loops, wherein the spacer region hybridizes to a nucleotide sequence complementary to a target sequence adjacent to a 5′-end of a protospacer adjacent motif (PAM), and wherein the target sequence and the PAM are located within 1 kilobase (kb) of the transcriptional start site (TSS) of a TCF4 gene.

A gene editing system comprising:

(i) a first nucleotide molecule encoding a first half of a split catalytically inactive Cas9 (dCas9) protein fused to a mini VP64-p65-Rta (miniVPR) transcriptional activator and a first half of an intein;
(ii) a second nucleotide molecule encoding a second half of the split dCas9 fused to a second half of an intein and further encoding an MS2-P65-HSF1 (MPH) transcriptional activation complex;
and
(iii) a third nucleotide molecule encoding at least one small guide RNA (sgRNA) comprising a scaffold region and a spacer region, wherein the scaffold region comprises MS2 stem loops, wherein the spacer region hybridizes to a nucleotide sequence complementary to a target sequence adjacent to a 5′-end of a protospacer adjacent motif (PAM), and wherein the target sequence and the PAM are located within 1 kilobase (kb) of the transcriptional start site (TSS) of a TCF4 gene,
wherein when the split dCas9 encoded by the first nucleotide is transpliced with the split dCas9 encoded by the third nucleotide produces a complete dCas9.

2 more elements

Dependencies are inferred from the claim text.

Facts

Application

19/483,254Filed 15 May 2024

Priority

15 May 2023

Published

8 Oct 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

A61K 48/005
Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy:…
A61K 38/1709
From vertebrates: from mammals
A61K 48/0075
Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy:…
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…

Transcription factor 4 gene editing system

Life of this patent

Transcription factor 4 gene editing system

Life of this patent

Abstract

Claims22