Progeria

New drug treatments on the horizon

Until recently, there was no specific treatment for Hutchinson-Gilford Progeria Syndrome (HGPS), but a clinical trial at Boston Children’s hospital, funded by the Progeria Research Foundation, has reported encouraging results with a drug called lonafarnib, an oral medication known as a farnesyl transferase inhibitor (FTI).

Lonafarnib was originally tested as a treatment for malignant brain tumors. Mark Kieran, MD, PhD, director of pediatric medical neuro-oncology at the Dana-Farber/Children’s Hospital Cancer Center, was familiar with lonafarnib’s chemical properties and had observed its safety profile in children, so was chosen by the Progeria Research Foundation to lead a clinical trial of the drug at Boston Children’s Hospital.

All 26 children in the two-year study, conducted at Boston Children’s Clinical and Translational Study Unit, showed improvements in at least some of these aspects of the disease:

• Weight gain: One in three children had a more than 50 percent increase in annual rate of weight gain, or switched from weight loss to weight gain, because of increased muscle and bone mass. Some children continued to lose weight, however.

• Bone structure: On average, skeletal rigidity improved to normal levels, and many children also had improvements in bone density.

• Cardiovascular signs: Stiffness of the arteries, a risk factor for heart attack and stroke that increases with age, decreased by 35 percent.  Vessel wall density also improved.

• Improvements in hearing

How does lonafarnib work?

Lonafarnib works by preventing a molecule called a farnesyl group from attaching to progerin (the protein that’s abnormal in children with progeria). This, in turn, prevents progerin from building up on the membrane of the cell nucleus; instead, progerin floats freely outside the nucleus where it seems to do less damage. We think this may help prevent some signs of premature aging.

In healthy patients, the body is able to remove the farnesyl group when it’s no longer needed. In progeria, since the farnesyl group can’t be removed, lonafarnib prevents it from being added in the first place.

Are there other drugs that can help with progeria?

A second clinical trial at Boston Children’s, funded by PRF and the National Institutes of Health, is now close to completion. This study is adding two drugs to lonafarnib in patients with HGPS:

• Pravastatin (marketed as Pravachol or Selektine), a “statin” drug that is usually used to lower cholesterol and prevent cardiovascular disease

• Zoledronic acid, abisphosphonate, usually used as a bone drug for improving osteoporosis and to prevent bone fractures.

Boston Children’s also hopes to launch a trial that would add a fourth drug, closely related to existing drug rapamycin, in the near future. Rapamycin has already been used in children for other indications, such as preventing organ rejection after transplant, and its safety profile is well known.

(Adapted from information compiled by the Progeria Research Foundation.)