Gene therapy with lipoprotein lipase variant S447X.

Variant S447X To the Editor: Ross et al recently reported a dazzling series of in vivo experiments1 showing reversal of abnormal biochemical phenotypes in Lpl / mice through adenoviral-mediated gene transfer of the socalled “gain-of-function” S447X prematurely truncated human variant of lipoprotein lipase (LPL or LIPD). Furthermore, all readouts in lipase-deficient mice treated with this human variant were at least as good as (and usually better than) those in mice treated with wild-type human LPL,1 providing some of the best evidence to date for a “gain-of-function” associated with this human variant, albeit in mice. These experiments offer hope for LPL-deficient patients, whose life quality and duration are compromised by their dyslipidemia. Indeed, somatic gene transfer experiments using adeno-associated virus (AAV) to deliver S447X (AAV1-LPL ) into the muscle of some patients with elevated plasma triglycerides (TGs) and low plasma LPL activity are underway.2,3 As this groundbreaking work proceeds, 2 points are worth remembering. First, the LPL S447X variant was initially discovered in patients with severe hypertriglyceridemia through genomic DNA screening experiments that were designed to detect loss-of-function mutations in LPL.4 One of these was my patient: a heterozygous woman of European ancestry 45 years of age with fasting chylomicronemia and recurring pancreatitis, whose plasma TGs ranged between 25 and 80 mmol/L despite good compliance with a low-fat diet and fibrate therapy. Her APOC2 was normal and her plasma postheparin LPL activity was 50% of normal, similar to some patients in whom AAV1-LPL S447X therapy is being contemplated.2,3 She had no other mutations in LPL and or in any other gene so far studied. In fact, S447X was originally implicated as being causative for her dyslipidemia, before its presence in many completely healthy individuals implied that it must be a normal variant.4 Another patient, a 30-year-old female, had plasma triglycerides ranging between 30 and 100 mmol/L and recurring pancreatitis, with depressed postheparin LPL activity and normal APOC2; she was a compound heterozygote for the LDL loss-of-function mutation G188E on one allele and S447X on the other allele. Thus, suggestions that somatic transfer of AAV1-LPL S447X may help patients with LPL deficiency and perhaps those with other molecular forms of hypertriglyceridemia5 must be considered with caution. Certainly, germline presence of S447X did not protect some patients against severe hypertriglyceridemia.4 Patients with pure homozygous molecularly proven LPL deficiency (ie, analogues of the Lpl / mouse) rather than those with other forms of hypertriglyceridemia would be expected to benefit the most. The second point is that without parallel-blinded somatic transfer using wild-type LPL, any benefit observed with somatic transfer of AAV1-LPL S447X will not resolve the issue, which, for some of us, is still contentious of whether S447X really has a biologically or clinically meaningful “beneficial” or “gain-of-function” advantage over wild-type LPL in humans. Persistent attribution of a “gain-offunction” to this nonsense variant during human somatic gene transfer experiments in the absence of appropriate controls with wild-type LPL might be unintentionally misleading, especially if it is ever shown that similar clinical outcomes could have been achieved using the wild-type LPL gene.