Conditions: Progeria Hutchinson-Gilford Syndrome
Keywords: Hutchinson-Gilford Progeria Syndrome HGPS Progeria FTI Farnesyltransferase Inhibitor Lonafarnib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This is an open label dose adjusted phase II trial of the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH66336) for patients with HGPS and progeroid laminopathies.

Detailed description:
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 function.

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 compound.

Arms:
arm 1: All subjects initiated oral Lonafarnib twice daily at a dose of 115mg/m2 and escalated to 150 mg/m2. Two subjects de-escalated to 115mg/m2 following toxicity.

Interventions: intervention 1: Lonafarnib
Intervention descriptions: intervention 1: Lonafarnib will be taken orally, twice per day, by all patients enrolled on this study. The drug is supplied to patients in capsule form, and for patients who are unable to swallow pills, the drug may be dissolved into solution. Every patient will start lonafarnib therapy at a dose of 115mg/kg. The study allows for patients to receive a dose escalation (up to 150mg/kg) if the drug is being well-tolerated. Every patient enrolled on this study will undergo two years of lonafarnib therapy.

Protocol document: