Progeria Improves With an Experimental Cancer Drug

Ricki Lewis, PhD

September 27, 2012

September 27, 2012 — A farnesyltransferase inhibitor originally intended to treat cancer has improved the conditions of all 25 children in a clinical trial for the rapid-aging disorder Hutchinson-Gilford progeria syndrome (HGPS), according to a report published online September 24 in the Proceedings of the National Academy of Sciences.

Leslie B. Gordon, MD, PhD, from the Department of Anesthesia, the Division of Critical Care Medicine, Boston Children’s Hospital and Harvard Medical School, Massachusetts, and the Department of Pediatrics, Hasbro Children’s Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, and colleagues conducted a prospective single-group open-label clinical trial in which each participant served as his or her own control for the primary outcome: rate of weight gain. Dr. Gordon is the founder and medical director of the Progeria Research Foundation and has a child who has HGPS.

HGPS is an autosomal dominant condition that arises as a new mutation during spermatogenesis. The syndrome accelerates certain features of aging, including extreme failure to thrive, lipoatrophy, hardened skin, joint contractures, alopecia, skeletal dysplasia, and severe atherosclerosis. Children with the most severe form of progeria, HGPS, die at an average age of 13 years from myocardial infarction or stroke. It is an untreatable, uniformly fatal disease.

Discovery of the mutation that causes HGPS in 2003 opened the door for rational treatment. A splice variant of the LMNA gene deletes 50 amino acids from the protein lamin A, forming progerin. The abnormal protein lacks the cleavage site from which the farnesylated carboxy terminus is usually removed posttranslation (farnesyl is an organic functional group). Progerin accumulates in the inner nuclear membrane, where it interferes with chromatin in a way that generates a highly consistent phenotype of rapid aging.

Farnesyltransferase inhibitors prevent attachment of farnesyl to progerin, essentially blocking formation of the disease-causing protein.

Lonafarnib, an experimental drug donated by Merck, corrected the phenotype in patient fibroblasts in culture, and then in mouse models, where it extended life and improved bone mineralization and cardiovascular function. Lonafarnib was developed to treat pediatric brain cancer.

The 25 children in the trial came from 16 countries and accounted for 75% of the HGPS cases known in the world at the time the study started. Each child received lonafarnib orally twice a day for at least 2 years.

The primary outcome was alteration of linear weight gain, which is highly stable within a child. The trial defined success as an increase of 50% over pretherapy rate. Secondary outcomes included cardiovascular changes, as measured with arterial pulse wave velocity and carotid artery echodensity, and changes in skeletal rigidity, bone mineral density, and sensorineural hearing.

Nine patients experienced a greater than 50% increase in the rate of weight gain, 6 had a greater than 50% decrease, and 10 remained stable. Nausea and diarrhoea associated with the drug may have countered some weight gain.

Results for the secondary outcomes were highly encouraging. Before treatment, carotid-femoral pulse wave velocity exceeded pediatric norms 3.5-fold because of the stiffened arteries characteristic of the disease. At the end of the study, pulse wave velocity had decreased by a median of 35%. Echodensity of the intima media and near and deep adventitia of the carotid arteries decreased as well, indicating less stiffness.

In 11 children who could be tested, bone rigidity at 4 sites in the radius improved to normal levels. Bone bending strength also improved. In areal bone mineral density measured for total body, hip, and spine, 2 children improved in all 3 sites, 10 children improved in 2 of the 3 sites, and 7 children improved at a single site. Eight children had better sensorineural hearing.

Overall, each patient improved in some way. Limitations of the study, the researchers write, included the small sample and the lack of longitudinal data because of the rarity of the disease; the fragility of the children, which precludes certain procedures to evaluate responses; and the inability to assess morbidity in the 2-year timeframe.

"Given the fact that the researchers are dealing with a disease with a frequency of around 1 in a million and with a typical mortality at around age 13, they did an amazingly efficient job of capturing the best sample size possible at the time. Much more informative are the results on assays that reflect cardiovascular function and bone structure," George M. Martin, MD, professor emeritus of pathology at the University of Washington, Seattle, told Medscape Medical News.

Implications transcend patients with the ultrarare HGPS. " also produced in normal individuals and increases with age," the researchers write.

"An important avenue of research will be to determine if there are human genotypes that are particularly vulnerable to the creation of this minor isoform of lamin A and if such individuals are particularly prone to myocardial infarction. Farnesyltransferase inhibitors might ameliorate the progression of atherosclerosis, the most important disease of our society," Dr. Martin told Medscape Medical News.

Two coauthors are employees of Merck Pharmaceuticals. Dr. Martin has disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online September 24, 2012. Full text