|Dr. Mark Kieran of Children’s Hospital Boston discusses the challenges of conducting clinical trials with progeria patients.
NIH staff and grantees were in abundance at the Progeria Research Foundation’s 10th anniversary workshop in Boston. Basic researchers and clinicians alike gathered to share their latest findings on Hutchinson-Gilford progeria syndrome, a fatal childhood disease that resembles accelerated aging.
Children with progeria remain small, lose their hair and fat, suffer from stiff joints and have myriad other symptoms that seem to mix developmental and aging problems. They develop cardiovascular disease and typically die of heart attacks and strokes at an average age of 13. There is no cure. But the disease doesn’t affect their mental or social development; they think and act like normal kids.
Progeria occurs in an estimated 1 in 4 million births and just 63 children in the world are known to have it. It’s caused by a single nucleotide mutation in a gene called LMNA (pronounced like one of the proteins it makes, “lamin A”). NIH director Dr. Francis Collins headed one of the two labs that discovered the mutation in 2003, and his lab continues to study the disease today.
The 2-day workshop, partially funded by NHLBI and NIH’s Office of Rare Diseases Research, featured a panel of affected families who described daily life with progeria and answered questions from the audience.
Progeria Research Foundation medical director Dr. Leslie Gordon delivered a keynote address looking back at past accomplishments and ahead to the challenges of drug development and the possibility of gene or stem cell therapies. Gordon launched the foundation after her son was diagnosed with progeria in 1998 and has been credited with establishing the resources and pulling together the top researchers needed to make progress in this exceptionally rare disease.
The workshop also included presentations from two teams conducting the world’s first clinical trials for progeria treatment. Dr. Mark Kieran and his team at Children’s Hospital Boston discussed the challenges of designing non-placebo-controlled trials with such a small population of patients as well as the process of characterizing the disease, including observations of the children’s weight, teeth, skin, bones and blood vessels. In 2009, Kieran received a $1.7 million “Grand Opportunities” grant from NHLBI and the NIH Office of the Director to conduct the team’s third trial, which is testing a combination of three drugs.
Dr. Nicolas Lévy followed up with preliminary results from the two-drug clinical trial his team is conducting in Marseille, France.
|Twelve-year-old Hayley Okines (r) and her mom, Kerry, during the family panel
On the “bench” side of the spectrum, Northwestern University cell biologist and longtime NIH grantee Dr. Robert Goldman chaired a session that delved into the basic science of progeria. He described the critical interplay between basic and clinical science in understanding and treating the disease. On the one hand, he said, because progeria disrupts a lamin protein found in cell nuclei, the disease offers “entirely new insight into nuclear structure and function” as well as chromatin organization and gene expression.
At the same time, he added, having a body of research already established on lamins when progeria was first linked to the LMNA gene allowed the progeria research community to hit the ground running.
“If it weren’t for the NIH and NSF and a few other government agencies fostering and encouraging basic science, the drug trials would not be where they are today,” Goldman said. “We have to thank the government for allowing [basic researchers] to pursue our untargeted research studies in the area of proteins like lamins.”
“Understanding the treatment of any disease relies on basic research,” added NCI senior investigator and fellow workshop advisory board member Dr. Tom Misteli. “I think we’re going to see more of this in the future—as more disease genes are being identified, all of a sudden you can tap into the knowledge that’s generated from basic research.”
At the workshop, Misteli spoke about high-throughput screening his lab is conducting to find a small-molecule drug that would selectively block progeria’s faulty gene splicing and stop production of the mutated protein.
Other highlights included presentations by former NHLBI director Dr. Elizabeth Nabel, now president of Brigham and Women’s Hospital, whose NIH intramural lab is wrapping up investigations into the nature of the children’s cardiovascular disease and its relationship to the cardiovascular disease millions of people experience as they age; and NIA grantee Dr. Judith Campisi, who is exploring the connection between cellular senescence in progeria and natural aging.