Progeria or Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder characterized by accelerated aging. Caused by a mutation in the LMNA gene, it leads to the accumulation of the toxic protein Progerin, resulting in severe cardiovascular issues and a life expectancy averaging 14.5 years. Progerin disrupts nuclear structure and function, causing various cellular abnormalities. There is no cure for Progeria, but there are treatments that can help manage symptoms and complications. Treatments include
- Farnesyltransferase Inhibitors (FTIs): Lonafarnib has shown promise in reducing mortality rates in pediatric progeria patients. However, since farnesylation is vital for several proteins, potential side effects have delayed broader clinical studies.
- Antisense Oligonucleotides: These are designed to prevent the synthesis of mutant progerin by binding to specific mRNA sequences associated with the LMNA mutation. This approach has improved cellular conditions and restored nuclear morphology in affected cells.
- Trans-Retinoic Acid and Rapamycin: This combination has demonstrated effectiveness in restoring normal phenotypes in progeria patient fibroblasts by suppressing LMNA activity and promoting normal cellular functions
- Gene Therapy: Techniques like CRISPR/Cas9 aim to edit the mutant LMNA gene directly. Early studies showed restored nuclear shape and increased lifespan in progeria mouse models. Advanced methods, such as adenine deaminase systems, have achieved higher editing efficiencies and normalization of cell morphology.
- Targeting Existing Progerin: Treatments like rapamycin activate autophagy, enabling cells to clear accumulated progerin, thereby addressing the harmful effects of existing progerin in cells.
Image: Current clinical Studies and Small Molecules used in treatment of Progeria; Key players playing role in Therapeutic Market
Progerinin, developed by PRG Science & Technology Co., Ltd. with support from The Progeria Research Foundation (PRF), is currently undergoing a Phase 2a trial in combination with the approved treatment Zokinvy, which blocks progerin formation. Research indicates that Zokinvy can extend lifespan in Progeria mouse models by 25%, while Progerinin shows potential for a 50% increase. The trial, a collaborative effort involving PRG S&T, PRF, and Boston Children’s Hospital, underscores a commitment to enhancing treatment options for patients. With around 400-450 children affected globally, insights from Progeria research may also inform treatments for age-related diseases, particularly cardiovascular conditions. PRF, established in 1999, has been pivotal in Progeria research, maintaining an international patient registry and funding clinical trials to develop effective therapies, ultimately aiming to improve the lives of children with Progeria while exploring broader implications for the aging population.
While these approaches are promising, challenges remain, particularly in achieving widespread delivery of therapies and effectively targeting terminally differentiated cells. Further research is needed to fully prevent progerin production and eliminate existing progerin.
Dr. Malini Gupta, Ph.D.
Sources
- https://rarediseases.org/rare-diseases/hutchinson-gilford-progeria/
- https://www.progeriaresearch.org/
- https://www.orpha.net/en/disease/detail/740
- https://link.springer.com/article/10.1134/S0026893322020091#Fig3 – used in figure
- https://www.sciencedirect.com/science/article/pii/S0188440923000759
- https://www.newswire.com/news/us-fda-authorizes-launch-of-clinical-trial-to-support-new-treatment-22434287
- https://www.biospace.com/fda/us-fda-authorizes-launch-of-clinical-trial-to-support-new-treatment-development-for-progeria#
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