阻断特殊基因就可帮助减肥

  来自蒙特利尔大学的研究人员近日通过阻断患者机体特定基因的表达，结果发现这可以有效降低患者血液中的甘油三酯浓度，即使是在各种形式的高甘油三酯血症患者中均可以实现降低甘油三酯水平的目的，这种特殊基因可以编码一种名为apoC-III的蛋白。
  研究者Daniel Gaudet指出，本文研究发现蛋白apoC-III在甘油三酯的管理上扮演着重要角色，而甘油三酯就好比是胆固醇一样是一种脂质，其通常来源于饮食中的脂肪或机体产生的，血液中甘油三酯的积累常常和心血管疾病及胰腺疾病发病风险增加直接相关，而本文研究对于后期开发抑制和甘油三酯相关的疾病的发生直接相关。
  研究成果发表于国际杂志NEJM上，尽管罕见的遗传性甘油三酯积累形式的确存在，而且目前疗法家少；高甘油三酯血症常常和机体贫乏的健康问题相关，比如肥胖、糖尿病等。去年12月发表在NEJM上的一篇研究报道就表明，阻断编码apoC-III蛋白的基因的表达就会有效降低高甘油三酯血症患者机体甘油三酯的浓度。
  而本文研究中研究者发现，apoC-III蛋白对于机体有效控制血脂扮演了重要的作用，而解析该蛋白所涉及的分子机制或可帮助开发精细个体化的干预措施来有效抑制多种严重形式的高甘油三酯血症。最后研究者Gaudet说道，本文研究或可加速靶向疗法的开发来帮助有效控制高甘油三酯血症的发生，同时也为减肥疗法的开发带来曙光。（转化医学网360zhyx.com）
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Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia
NEJM   DOI: 10.1056/NEJMoa1400283
Daniel Gaudet, M.D., Ph.D., Veronica J. Alexander, Ph.D., Brenda F. Baker, Ph.D., Diane Brisson, Ph.D., Karine Tremblay, Ph.D., Walter Singleton, M.D., Richard S. Geary, Ph.D., Steven G. Hughes, M.B., B.S., Nicholas J. Viney, B.Sc., Mark J. Graham, M.S., Rosanne M. Crooke, Ph.D., Joseph L. Witztum, M.D., John D. Brunzell, M.D., and John J.P. Kastelein, M.D., Ph.D.
BACKGROUND
Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.
METHODS
We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801–fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.
RESULTS
A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801–fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.
CONCLUSIONS
We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.)


Targeting APOC3 in the Familial Chylomicronemia Syndrome
NEJM    DOI: 10.1056/NEJMoa1400284
Daniel Gaudet, M.D., Ph.D., Diane Brisson, Ph.D., Karine Tremblay, Ph.D., Veronica J. Alexander, Ph.D., Walter Singleton, M.D., Steven G. Hughes, M.B., B.S., Richard S. Geary, Ph.D., Brenda F. Baker, Ph.D., Mark J. Graham, M.S., Rosanne M. Crooke, Ph.D., and Joseph L. Witztum, M.D.
The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.