Clinical Insight into Xi-chromosome Reactivation and its Therapeutic Potential in X-linked cardiomyopathies and related disorders.

Dr Ng, Kwong Man   (Principal Investigator (PI))

Professor Tse Hung Fat   (Co-Investigator)

24

2018-01-01

784800

Clinical Insight into Xi-chromosome Reactivation and its Therapeutic Potential in X-linked cardiomyopathies and related disorders.

Drug testing and screening, Isogenic iPSCs, X-chromosome inactivation, Xi-chromosome reactivation, X-linked cardiomyopathies

Cardiovascular Research,Drug Discovery and Delivery

Biology and Medicine (M)

17106917

General Research Fund (GRF)

2017

Completed

1 To evaluate and compare the efficacy of different DNA-demethylating agents in reactivating the Xi-chromosome and reducing the cardiac dysfunction associated with LAMP2-deficiency. This will be accomplished by treating heterozygous iPSCs (and the iPSCs-CMs), that carry the silenced LAMP2 allele with different existing DNA-methylation inhibitors. Alterations in LAMP2 protein production and cardiac function will be evaluated to assess their therapeutic efficacy. Any potential cellular toxicity caused by these drugs will also be evaluated 2 To test if the experimental data obtained from the LAMP2-deficient iPSC platform can be applied to other X-linked cardiomyopathies. This will be accomplished by the generation of isogenic iPSC lines from heterozygous female carriers of other X-linked cardiomyopathy-associated mutations to test the drugs used in Objective 1. 3 To create a clinically relevant platform for the identification of novel Xi-chromosome reactivating drugs. This will be accomplished by subjecting iPSCs that carry the silenced wild-type LAMP2 allele to a library of small molecules followed by evaluation of the restoration of LAMP2 protein production. Any putative drugs identified in the initial screening will be further evaluated for their ability to improve cardiac function.