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Compositions and methods for treating or preventing catecholaminergic polymorphic ventricular tachycardia

A technology of composition and medicine, applied in the field of treatment of CPVT and medicine for treatment of CPVT, which can solve the problems of limited patient compliance and side effects

Pending Publication Date: 2020-05-22
CHILDRENS MEDICAL CENT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these treatments are not effective for all patients and are limited by patient compliance, drug side effects, or the risk of adverse events such as fatal electrical storms caused by implantable defibrillators

Method used

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  • Compositions and methods for treating or preventing catecholaminergic polymorphic ventricular tachycardia
  • Compositions and methods for treating or preventing catecholaminergic polymorphic ventricular tachycardia
  • Compositions and methods for treating or preventing catecholaminergic polymorphic ventricular tachycardia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] Example 1: Isogenic CPVT (PGP1-RYR2 R4651I )

[0266] Skin fibroblasts were obtained from CPVT patients. This patient had a normal resting ECG but exercise-induced polymorphic ventricular tachycardia. Genotyping revealed that this patient had a point mutation in RYR2, resulting in the replacement of arginine at position 4651 with isoleucine (R4651I; Figure 19A to Figure 19C ). Clinical genotyping did not implicate other candidate genetic arrhythmia genes. Fibroblasts were reprogrammed into iPSCs (CPVTp line, where p means patient-derived; Figure 20A to Figure 20D ), which robustly differentiated into iPSC-CMs with an efficiency comparable to that of the wild-type iPSC line PGP1 ( Figure 1A , Figure 20E to Figure 20F ). Introducing patient mutations into PGP1 using Cas9 genome editing resulted in an isogenic CPVT line (PGP1-RYR2 R4651I , abbreviated as CPVTe, where e stands for engineered) and the control line (PGP1, abbreviated as WT) ( Figure 20G ).

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Embodiment 2

[0278] Example 2: AIP inhibits arrhythmia in CPVT mouse model

[0279] As reported above, AIP selectively inhibited CPVT in an opto-MTF model expressing the R4561I mutation. To determine in vivo potency, an adenoviral vector encoding the CaMKII inhibitory peptide Autocamtide (AIP) linked to GFP was generated. This adenoviral vector was injected intraperitoneally into mice ( Figure 6H ). Such as Figure 7 As shown, AIPGFP expression was observed in mouse myocardial tissue. Micrographs of myocardial tissue showing localization of AIP-GFP expression. Approximately 16% of troponin-positive cells expressed low levels of GFP, while the vast majority of troponin-positive cells expressed GFP at higher levels ( Figure 8 , left). AIP expression in troponin-positive cells was also quantified ( Figure 8 , right). Most cells express AIP linked to GFP at moderate or high levels.

[0280] In response to isoproterenol stimulation, AIP expression was sufficient to inhibit phosphory...

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Abstract

The present invention features AIP peptide and polynucleotide compositions, methods of using such compositions for the treatment of CPVT, as well as a human induced pluripotent stem cell derived cardiomyocyte model, useful in characterizing agents that modulate myocardial conduction and contraction.

Description

[0001] Cross References to Related Applications [0002] This application is an international application designating the United States and claims the benefit of U.S. Provisional Application 62 / 529,256, filed July 6, 2017, the contents of which are hereby incorporated by reference in their entirety, based on 35 U.S.C. § 119(e) . [0003] Statement of Rights in Inventions Made Under Federally Sponsored Research [0004] This invention was made with government support funded by the National Institutes of Health (Grant Numbers: NIH U01H1100401 and UG3 TR002145). The government has certain rights in this invention. Background technique [0005] Catecholamine-sensitive polymorphic ventricular tachycardia (CPVT) is a condition characterized by abnormal heart rhythms with a prevalence of up to 1 in 10,000. Symptoms of CPVT include dizziness or fainting associated with exercise or emotional stress. Episodes of ventricular tachycardia can effectively stop the beating of the heart (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/18A61K31/404A61K31/42A61K31/426A61K31/4439A61K31/454
CPCA61K38/005C07K14/4703C07K14/705C12N5/0657C12N5/0696C12N9/12C12N15/86C12N2501/602C12N2501/603C12N2501/604C12N2501/999C12N2506/1307C12N2506/45C12N2510/00C12N2533/12C12N2533/54C12N2533/90C12N2710/10343C12N2740/16043C12N2750/14143C12Y207/11017G01N33/5073G01N2500/10A61P9/06A61K38/00C12N7/00C12N2750/14171G01N33/5061
Inventor W·普V·比兹泽里德斯D·张
Owner CHILDRENS MEDICAL CENT CORP
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