New RNA therapy reverses symptoms of progeria in mouse models

Children who develop deep wrinkles, stunted growth, and rapidly aging bones and blood vessels as early as 1 to 2 years of age may be suffering from Hutchinson-Gilford Progeria Syndrome (HGPS), a rare and incurable genetic disorder that affects approximately one in eight million people. The average life expectancy for patients is just 14.5 years, and to date, no curative treatment exists.

The only FDA-approved drug for progeria, lonafarnib (Zokinvy), comes at an extraordinary cost-approximately 1.4 billion KRW (USD 1 million) per dose-and provides only a modest life extension of 2.5 years. The treatment often requires combination with other therapies and carries the risk of significant side effects, underscoring the urgent need for more effective and safer therapeutic options.

A research team led by Dr. Sun-Uk Kim at the Center for Next-Generation Animal Resources, Korea Research Institute of Bioscience and Biotechnology (KRIBB), has successfully developed the world's first precision RNA-targeting therapy for progeria using next-generation gene regulation technology. Their novel approach selectively eliminates disease-causing RNA transcripts while preserving the function of normal genes, significantly improving safety and opening new possibilities for treatment.

HGPS is caused by a single-point mutation in the LMNA gene, which leads to the production of progerin, a toxic, abnormal protein. Progerin disrupts the structure of the nuclear envelope in cells, accelerating cellular aging and causing symptoms similar to advanced aging-brittle bones, stiffened arteries, and ultimately, failure of vital organs.

To counter this, Dr. Kim's team engineered an RNA-guided molecular "scissors" based on RfxCas13d (paired with a custom-designed progerin gRNA). This precision tool distinguishes mutant RNA from normal transcripts, enabling selective degradation of progerin while sparing healthy lamin A proteins.

Unlike traditional gene-editing methods like CRISPR-Cas9, which permanently alter DNA and pose risks of off-target mutations, this RNA-targeting strategy modifies only RNA. It thus offers a higher safety profile and even allows reversibility in the event of unintended effects.

When applied to a mouse model carrying the progeria mutation, the therapy significantly reversed hallmark disease symptoms-including hair loss, skin atrophy, spinal curvature, and impaired mobility. Treated mice also showed restored body weight, reproductive organ function, and improved heart and muscle health-resembling the condition of healthy controls.

Beyond treating progeria, the study also points to the potential for precise regulation of aging processes. The researchers found that progerin levels increase naturally in aged human skin cells, and the application of the RNA-targeting tool helped delay certain signs of aging in these cells.

This technology is not only applicable to Hutchinson-Gilford Progeria Syndrome but also holds therapeutic potential for over 15% of genetic disorders caused by RNA editing errors." He added, "We expect this to evolve into a versatile platform technology with broad applicability to age-related diseases, cancer, and neurodegenerative disorders."

Dr. Sun-Uk Kim, lead researcher

Korea Research Institute of Bioscience and Biotechnology (KRIBB) is a leading national research institute in South Korea dedicated to cutting-edge research in biotechnology and life sciences. Established in 1985, KRIBB focuses on advancing scientific knowledge in areas such as molecular biology, genomics, bioinformatics, synthetic biology, and aging-related studies. As a government-funded institute, KRIBB plays a pivotal role in driving innovation, supporting national R&D strategies, and collaborating with academic and industrial partners both domestically and internationally.

This research was supported by Big Issue Group Program(KRIBB Research Initiative Program) and the Global TOP Program funded by the National Research Council of Science & Technology (NST), the Excellent Young Researcher Program under the Basic Science Research Program of the Ministry of Science and ICT (MSIT), and the Core Technology Development Program for the Bio-Industry of the Ministry of Trade, Industry and Energy (MOTIE).