The first drug was approved Friday for a rare genetic disorder that stunts growth and causes rapid aging in children, after studies showed it can extend their lives.
Kids with the genetic disorder progeria typically die in their early teens, usually from heart disease. But in testing, children taking the drug Zokinvy lived 2 1/2 years longer on average.
The U.S. Food and Drug Administration approved the capsules for progeria and a related condition.
Research on the treatment was mainly funded by the Progeria Research Foundation in Peabody, Massachusetts, with help from drug developer Eiger BioPharmaceuticals.
“This is just the first. We’ll find more and better treatments,” said Dr. Leslie Gordon, the foundation’s medical director.
Gordon, a pediatric disease researcher at Hasbro Children’s Hospital in Providence, Rhode Island, created the foundation in 1999 with her sister and husband, soon after their son Sam was diagnosed. He died in 2014 at age 17.
Just an estimated 400 people worldwide have progeria or its related condition, including 20 in the U.S. The disorder causes stunted growth, stiff joints, hair loss and aged-looking skin.
Children with the disease suffer strokes and hardening of heart arteries, and die at 14 1/2 on average.
The disorder is not inherited but due to a chance gene mutation that causes a damaging buildup in cells of a protein called progerin, for which the disorder is named. The drug blocks production and accumulation of the protein, slowing its damage and the premature aging.
Until testing began in 2007, doctors could only try to ease some symptoms.
Meghan Waldron of Deerfield, Massachusetts, was diagnosed with progeria by age 2. She wasn’t growing or gaining weight and her hair was falling out. She was one of the first children to get the drug.
“Pretty soon,” she said, “there were obvious improvements.”
She started growing a little more—she’s now 3 feet, 7 inches tall—and tests showed a slowing of hardening of her arteries.
The 19-year-old Waldron backpacked in Europe alone last year after graduation from high school, where she ran track and cross country.
“My physical health is pretty good,” other than some joint stiffness, said Waldron, a sophomore creative writing student at Emerson College in Boston. “It’s just something I live with.”
She still takes the drug as part of a long-term follow-up study.
“I am so excited” about its approval, she said.
The FDA action was based on two studies in which a total of 62 kids took the drug twice a day. Their outcomes were compared with 81 untreated children around the world, matched by age and other characteristics.
The participants were followed for up to 11 years, and those who took the drug lived 2 1/2 years longer on average.
In all, four studies of the drug have been done at Boston Children’s Hospital, with 22 children and young adults taking the drug since 2010 or earlier. The oldest is 24 and has been taking it for 13 years.
Eiger, a small Palo Alto, California, drug developer, isn’t disclosing the price yet for Zokinvy, also known as lonafarnib, but it will be expensive since there are so few patients. Eiger will offer financial assistance so all patients can get it.
Zokinvy’s most common side effects were vomiting, diarrhea, nausea, abdominal pain and fatigue.
The foundation’s Gordon worked with National Institutes of Health Director Dr. Francis Collins on laboratory research that found the genetic cause of progeria in 2003.
She said research “coming up the pike” could possibly give patients “longer lives, stronger hearts and move towards a cure.”
Progeria is a rare genetic disease noticed in children characterized by premature aging that predominantly affects the skin, bones, and cardiovascular system.1 This syndrome affects one in 4–8 million births2 noticed throughout the world with no gender or ethnic biasness.2
The post-translational modifications observed in progerin were thought to demonstrate a predominant role in pathophysiology of the disease.3 The protein progerin is defined as a partially cleaved form of nuclear lamin A that is associated with the dysfunctional nuclear membrane and premature senescence.4
The Hutchinson–Gilford progeria syndrome (also called progeria) is a result of a dominant point mutation triggered in the nuclear lamin A gene that encodes major protein in exon 11 (C to T transition noticed at nucleotide 1824) leading to a silent mutation resulting in Gly608 → Gly608.4
The so formed mutant exhibits a new splicing donor site responsible for the formation of mutant lamin A protein termed progerin. Structurally, progerin is devoid of a proteolytic cleavage site essential for the elimination of the last 18 carboxyl-terminal amino acids to generate mature lamin A.4
Progerin accumulation within the nuclei leads to the disruption of the nuclear structure, thereby causing premature replicative senescence.5
Under such conditions, the farnesyltransferase inhibitors (FTIs) have proven to be of great potential against progeria.6
Farnesyltransferase inhibitors (FTIs) are small molecules that can bind reversibly to farnesyltransferase at the (cysteine–aliphatic amino acid–aliphatic amino acid–any amino acid) CAAX binding site, correspondingly hindering progerin farnesylation and intercalation into the membrane of the nucleus,7,8 thereby improving the cardiovascular and skeletal pathologies and weight gain.2,9
Lonafarnib, one of the FTIs that is widely used to treat progeria, has reached the clinical trials8,10 (https://clinicaltrials.gov/ct2/show/NCT00425607).
Initially developed to treat cancer,11 they typically act by reversing the nuclear abnormalities12,13 that are hallmark characteristics associated with progeria-affected children.
Encouraged by the beneficial effects of FTIs, there is a dire need to identify new drugs with similar abilities. Accordingly, in the current study, we focused on virtual screening for new chemical compounds that might have potential against progeria using the pharmacophore method.
In order to redeem the potential candidate compounds, the compound lonafarnib was considered. Since lonafarnib has exhibited encouraging results toward progeria, the current research intends to find small molecules that demonstrate the pharmacophore features (chemical features) that are manifested by lonafarnib.
In this pursuit, the investigation has proceeded by generating a pharmacophore model employing the small molecule lonafarnib. The obtained model was escalated to screen the chemical database to retrieve the compounds that map with the pharmacophore features.
A typical model incorporates a few features arranged in 3D form14 and should compose a repeated denominator of the molecular interaction features existing in a group of molecules. Thus, pharmacophore is defined as a pattern of features of a molecule that is responsible for a biological effect.14
Such pharmacophore models are upgraded to screen the small molecule chemical databases to obtain the compounds complementary to the pharmacophore features.15 When a small molecule fits into the pharmacophore spheres, they are termed Hits.14 The obtained Hits will be allowed to dock with the specific protein target to delineate the interactions between them at the atomic level16 and to predict the binding mode of the small molecules.17,18
The best poses from the molecular docking studies are thoroughly studied by molecular dynamics simulation studies to elucidate on the motions of atoms and molecules.19 The obtained results are read as root mean square deviation (RMSD), potential energy, radius of gyration (Rg), and the hydrogen bond number as described earlier.20
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