Minimal versatile genetic perturbation technology (mvGPT) showed promise in addressing human genetic diseases, including transthyretin amyloid cardiomyopathy (ATTR-CM), according to a study published recently in Nature Communications.
The study showed that the mvGPT platform integrated simultaneous gene editing, activation and silencing in human cells, offering hope for managing complex disorders such as ATTR-CM. With precise tools and multiple delivery methods, mvGPT has significant potential for transformative in vivo applications, the study said.
What is ATTR-CM?
Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a rare progressive disease of the heart muscle that leads to congestive heart failure. It occurs when the transthyretin protein produced by the liver is unstable. Symptoms include fatigue; shortness of breath; irregular heart rate or palpitations; swelling of the legs, ankles and stomach; brain fog; wheezing; and dizziness. It often goes underdiagnosed because of a lack of awareness and knowledge of the disease. There is currently no cure for ATTR-CM.
“Here, we present mvGPT, a streamlined and modular platform to perform simultaneous and orthogonal endogenous gene editing, activation, and repression in human cells,” the authors of this study said.
Read more about therapies for ATTR-CM
The mvGPT is a modular system designed to execute independent genomic and transcriptomic perturbations. It achieved precision using an engineered compact prime editor alongside a prime editing guide RNA and a nicking guide RNA. By incorporating advanced activator modules and a multiplex array to process RNAs for various genetic interventions, mvGPT enhanced its flexibility and effectiveness.
In ATTR-CM, mvGPT silenced the transthyretin gene, potentially reducing harmful amyloid deposition in cardiac tissues.
“mvGPT represents a compact and versatile molecular technology that enables effective simultaneous and orthogonal gene editing, activation, and repression in human cells, providing better support for the genetic interrogation of complex biology, the study of complex genetic diseases, and the development of human gene therapy,” the authors said.
These diverse applications highlighted mvGPT’s adaptability in addressing different therapeutic challenges. mvGPT successfully corrected a c.3207C>A mutation in the ATP7B gene, which is associated with Wilson’s disease, and upregulated expression of PDX1, a gene crucial for treatment of Type 1 diabetes.
Enhancements to the prime editing system have significantly increased efficiency. Researchers optimized nuclear localization signals and truncated reverse transcriptase domains to streamline the editor while maintaining robust activity. In addition, engineered pegRNAs improved stability and accuracy of editing, further advancing mvGPT’s capability to perform complex genomic modifications, the study said.
The technology also featured gene activation and transcriptional upregulation capabilities. By leveraging prime editors with MPH-recruiting single guide RNAs, mvGPT effectively boosted gene expression at target loci. This ability expanded its therapeutic range, enabling interventions for diseases requiring enhanced gene function.
Through its compact design, programmable nature and success across varied delivery methods, mvGPT could potentially pave the way for innovative genetic therapies, study authors said. Patients with ATTR-CM and other genetic conditions may benefit from future applications of mvGPT as the technology holds promise for accurate and effective disease management.
