An Open Label Dose Adjusted Phase II Trial of the Oral Farnesyltransferase Inhibitor (FTI) Lonafarnib (SCH66336) for Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) and Progeroid Laminopathies
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare "premature aging" disease in which all
children die at an average age of thirteen years (range 8-20 years) of severe
atherosclerosis leading to strokes and heart attacks. It is a multisystem disease with
objective clinical markers for disease progression. These include abnormalities in growth
and body composition, bone mineral density, joint function, endocrine function, alopecia,
and vascular disease. There is no effective therapy for any of the progressive and
deleterious aspects of this disorder.
The gene defect causing HGPS and most progeroid laminopathies has been identified as a
mutation in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally
expressed by most differentiated cells, and requires posttranslational farnesylation to
incorporate into the nuclear membrane. The lamin A C-terminal peptide, including the
farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of
the nuclear scaffold just internal to the nuclear membrane, affecting nuclear structure and
In most cases, HGPS is a sporadic autosomal dominant disease caused by a single base
alteration (henceforth designated as G608G) in the LMNA gene, which creates a cryptic splice
site giving rise to an altered lamin A protein product in which 50 amino acids are deleted.
The defective protein product in HGPS (henceforth progerin) lacks the cleavage site for
removal of the C-terminal farnesylated peptide, and likely produces disease via dominant
negative effects on the nuclear structure and function of various cell types that express
lamin A. Most other progeroid laminopathies are caused by various mutations in the LMNA
gene, which also subsequently creates abnormally functioning lamin A.
Lonafarnib is a farnesyltransferase inhibitor that blocks the post-translational
farnesylation of prelamin A and other proteins that are targets for farnesylation.
Farnesylation is essential for the function of both mutant and non-mutant lamin A proteins,
including progerin. Therefore, farnesyltransferase inhibitors are ideal candidates for
treatment of HGPS, which is caused by a protein (progerin) that likely depends on carrying a
farnesyl group to execute its aberrant functions.
Both cell culture and mouse model studies of HGPS demonstrate improved phenotype after
exposure to FTI. In vitro, exposure of HGPS skin fibroblasts and progerin-transfected HeLa
cells to FTIs, including lonafarnib, prevents preprogerin from intercalating into the
nuclear membrane where it normally functions, and eliminates nuclear deformity. In vivo,
three Progeria-like mouse models show no appreciable signs of toxicity after FTI
administration. In all three of these models, disease is significantly reduced when
compared to age-matched controls after oral administration of FTI.
We propose that clinical features of HGPS can be ameliorated or reversed by blocking
posttranslational farnesylation via treating patients with lonafarnib. We hypothesize that
reduction of the quantity of functional progerin or, in the case of other progeroid
laminopathies, other abnormal lamin proteins, will improve disease signs, symptoms and
outcome. We also hypothesize that the toxicity profile of FTI inhibition using lonafarnib
will be similar to that observed in children with malignant brain tumors treated with the
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the therapeutic effect of oral lonafarnib in patients with HGPS. Activity will be assessed by determining the change in rate of weight gain over baseline determined pre-therapy for each patient.
Duration of the study
Mark W Kieran, MD, PhD
Dana-Farber Cancer Institute, Children's Hospital Boston
United States: Food and Drug Administration
|Children's Hospital Boston||Boston, Massachusetts 02115|