The disclosure provides polypeptides comprising an engineered p27, or a fragment thereof. Such polypeptides may be used to form trimeric protein complexes with a cyclin-dependent kinase 4 (Cdk4) (or a variant thereof) or Cdk6 (or a variant thereof), and a cyclin D (CycD) or a variant thereof.

The present disclosure provides methods for inducing cell cycle reentry of postmitotic cell. The present disclosure further provides cells and compositions for treating diseases, such as cardiovascular diseases, neural disorders, hearing loss, and diabetes.

A gene editing system is provided that comprises a first nucleotide molecule encoding a dCas9-Ten-Eleven Translocation methylcytosine dioxygenase 1 catalytic domain (TET1CD) fusion protein; and a second nucleotide molecule encoding at least one small guide RNA (sgRNA), comprising: a scaffold region and a spacer region, 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 the CDKL5 gene. Methods of making and using the system are further described herein.

This present disclosure provides adeno-associated viral vectors, recombinant adeno-associated vims (rAAV), and methods of their use in gene therapy for treating CDKL5 deficiency disorder (CDD). Also provided are pharmaceutical compositions comprising an rAAV of the invention and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions may be useful in gene therapy for the treatment of CDD caused by mutations in CDKL.

This invention relates to a method for treating cancer by administering a CDK4/6 inhibitor or CDK2/4/6 inhibitor in combination with a 4-1BB agonist and/or an OX40 agonist to a subject in need thereof.

The present invention provides a method for detecting a target nucleic acid that discriminates the target nucleic acid from a non-target nucleic acid having a nucleotide sequence or modification state that differs from a portion of the target nucleic acid, the method comprising conducting a nucleic acid amplification reaction using a region in the non-target nucleic acid that differs from the target nucleic acid as a target region, using a region in the target nucleic acid that differs from the non-target nucleic acid as a corresponding target region, using a nucleic acid test sample as a template, and using a primer that hybridizes with both the target nucleic acid and the non-target nucleic acid, with the nucleic acid amplification reaction conducted in the presence of a molecule capable of binding specifically to the target region in the non-target nucleic acid, under temperature conditions under which the molecule can bind to the non-target nucleic acid, and then detecting the target nucleic acid on the basis of the presence or absence of an amplification product.

The invention is directed to methods of treating TNBC in a patient by administering to the patient an agent that inhibits the expression or activity of cyclin-dependent kinase 19 (CDK19). In some embodiments, the agent may be a small molecule inhibitor, a polynucleotide (e.g., shRNA. siRNA), or a protein (e.g., an antibody). In some embodiments, the agent does not inhibit the activity or expression of CDK8.

Provided are a novel compound having CDK8 and/or CDK19 inhibitory activity, and a production method for Tregs. The treatment of T cells with a CDK8 and/or CDK19 inhibitor induces Foxp3 in the T cells. Foxp3.sup.+ T cells can be induced by treating Foxp3.sup.− T cells with the CDK8 and/or CDK19 inhibitor in vitro. Thus, Tregs can be induced.

A method of sensitizing cancer to immunotherapy in a subject in need thereof includes administering to the subject a therapeutically effective amount of a CdK5 inhibitor to suppress immune checkpoint PD-L1.

Provided is a recombinant adeno-associated virus (rAAV) having an AAV capsid and a vector genome which comprises a nucleic acid sequence encoding a functional CDKL5 (hCDKLK5). Also provided are a production system useful for producing the rAAV, a pharmaceutical composition comprising the rAAV, and a method of treating a subject having CDD, or ameliorating symptoms of CDD, or delaying progression of CDD via administrating an effective amount of the rAAV to a subject in need thereof.