Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial.
We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.
ECOGENE-21 Clinical Research Center, Chicoutimi Hospital, Chicoutimi, QC, Canada. daniel.gaudet@umontreal.ca
D
D
Gaudet
J
J
Méthot
S
S
Déry
D
D
Brisson
C
C
Essiembre
G
G
Tremblay
K
K
Tremblay
J
J
de Wal
J
J
Twisk
N
N
van den Bulk
V
V
Sier-Ferreira
S
S
van Deventer
D000328:Adult; D000229:Dependovirus / Q000235:genetics; D004361:Drug Tolerance; D005215:Fasting / Q000097:blood; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000150:complications / Q000628:therapy*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010195:Pancreatitis / Q000150:complications; D011446:Prospective Studies; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D007166:Immunosuppressive Agents; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase