Progeria 101 / FAQ

Because of the historic Progeria gene discovery, we have a definitive, scientific way to diagnose the children. This results in more accurate and earlier diagnoses so they can receive proper care. The Progeria Research Foundation has a Diagnostic Testing Program that looks at the specific genetic change, or mutation, in the Progeria gene that leads to HGPS. After an initial clinical evaluation (looking at the child’s appearance and medical records), a sample of the child’s blood is tested for Progeria.  Genetic testing is also available at some genetic diagnostics facilities.  Accompanying genetic counseling is always advised.

Yes! History was made in September 2012, when the results of the first-ever Progeria clinical drug trial demonstrated that lonafarnib, a farnesyltransferase inhibitor (or FTI), was an effective treatment for Progeria[5]. All trial participants experienced significant improvements in weight gain, bone structure, and most importantly, the cardiovascular system.

Two subsequent studies, one from 2018 published in the Journal of the American Medical Association (JAMA)[6], and one from 2023 published in Circulation[7], demonstrated that lonafarnib helped extend survival in children with Progeria.

The 2012 and 2018 studies led to the extraordinary 2020 U.S. Food & Drug Administration (FDA) approval of lonafarnib, now branded as ‘Zokinvy,’ as the first-ever treatment for Progeria. A critical milestone in PRF’s mission, this approval was the culmination of 13 years of clinical research involving four clinical trials, bringing 96 children from 37 countries to Boston for treatment.

With this milestone, Progeria joined the ranks of fewer than 5% of rare diseases with an FDA-approved treatment.

Soon after the FDA approval of lonafarnib, the European Medicines Agency (EMA) approved lonafarnib for use in Europe in July 2022, followed by the Japanese Ministry of Health, Labor and Welfare (MHLW) in January 2024.

Without lonafarnib, the children die of atherosclerosis (heart failure or strokes) at an average age of 14.5 years [6] .  With long-term lonafarnib treatment, cardiovascular health is significantly improved, and life expectancy has been shown to increase by an average of 4.5 years7.  That’s more than a 30% increase in average lifespan, from 14.5 years to almost 20 years of age!

With the children living longer due to lonafarnib therapy, physicians are seeing aortic stenosis (narrowing of a critical heart valve) as a problem in the older children and young adults with Progeria that may be amenable to lifesaving surgery. In some cases, surgery to insert new heart valves or open blood vessels supplying the heart (stents) has helped to improve the health of patients in later stages of disease[8].

PRF is heavily involved in the development of three other therapeutic pathways, each of which has shown varying levels of increased lifespan when studied in Progeria mouse models – from 50% to an astonishing 140%!  Our goals are to discover new treatments that will work even better than lonafarnib alone, and to eventually cure Progeria by correcting the genetic mutation. We are targeting the disease at the protein, RNA and DNA levels.

1. DNA Base Editing: This pathway aims to permanently correct the Progeria gene mutation at the DNA level.
   In January 2021, the science journal Nature published breakthrough results demonstrating that genetic editing in a mouse model of Progeria corrected the Progeria mutation in many cells, improved several key disease symptoms and increased lifespan in the mice by 140%[9]. Additional preclinical studies are needed to investigate these results, which we hope will one day lead to a clinical trial.

“To see this dramatic response in our Progeria mouse model is one of the most exciting therapeutic developments I have been part of in 40 years as a physician-scientist,” said Francis Collins, MD, PhD.

2. RNA Therapeutics: This pathway aims to stop the production of progerin by correcting the genetic mutation at the RNA level.
   In March 2021, PRF contributed to two very exciting breakthrough studies on the use of RNA therapeutics, both of which attempt to block the body’s ability to produce progerin production at the RNA level. One study showed that treating Progeria mice with a drug named SRP2001 reduced the harmful progerin mRNA and protein expression in the aorta, the main artery in the body, as well as in other tissues. At the end of the study, the mice demonstrated an increased survival of 62%[10].
   The other study showed a 90 – 95% reduction of the toxic progerin-producing RNA in different tissues after treatment with a drug called LB143. Progerin protein reduction was most effective in the liver, with additional improvements in the heart and aorta.[11]This genetic correction is temporary, thus ongoing treatment to maintain the correction is required.
3. Small Molecule (Drugs): This pathway aims to reduce the level of the toxic progerin protein that causes Progeria.
   A drug called progerinin has shown great promise. In a Progeria mouse model, progerinin increased body weight and extended lifespan by 10 weeks, a substantial breakthrough, compared with lifespan extension of two weeks in lonafarnib-treated mice.[12]The field of Progeria research is making major advancements, continuously growing in scope and sophistication as the search for effective treatments and the cure continues. Brilliant, passionate researchers are leading the field to breakthroughs and new treatments that help children with Progeria live longer, healthier lives, while also driving discovery in heart disease and aging.In addition to exploration of new pathways toward treatments and the cure, in March 2023, PRF reported findings on the discovery of a Progeria biomarker, a new way to measure progerin, the toxic protein that causes Progeria. A biomarker has a game-changing capacity to unlock the promise of smarter and faster drug trials, and better treatments. Using blood plasma to measure progerin levels, researchers can understand how treatments are affecting clinical trial participants after a shorter period of time and at multiple points along each clinical trial, instead of relying on subjective clinical features.This test can optimize the clinical trial process by providing early information about the effectiveness of treatments being tested, as a lead-in to other clinical tests such as weight gain, dermatologic changes, joint contracture and function, etc., all of which require much more time to manifest. We may now be able to understand treatment benefits as early as four months after starting treatment, or stop a treatment that may not benefit the trial participant, to avoid unnecessary side effects.[13]