Pictured: A scale with DNA in the background/Taylor Tieden for BioSpace

图为：背景为DNA的天平/Taylor Tieden for BioSpace

Genetic therapies could help fight obesity, if early research at a few biopharma organizations and universities pans out. Preclinical studies indicate weight loss similar to that seen with GLP-1 agonists like semaglutide is possible but without some of the side effects, including muscle loss.

如果一些生物制药组织和大学的早期研究取得成功，基因疗法可能有助于对抗肥胖。临床前研究表明，体重减轻类似于GLP-1激动剂如semaglutide所见，但没有一些副作用，包括肌肉损失。

“With gene therapy, we see the potential for once-to-twice a year dosing . . . and to reduce fat, not reduce muscle,” said Paul Bolno CEO of Wave Life Sciences, which is conducting preclinical investigations into a gene therapy product for obesity.

Wave Life Sciences的首席执行官保罗·博尔诺（PaulBolno）说：“通过基因治疗，我们可以看到每年给药一到两次……并且可以减少脂肪，而不是减少肌肉。”Wave Life Sciences正在对一种治疗肥胖症的基因治疗产品进行临床前研究。

Obesity has become a global epidemic, affecting approximately 1 billion people, according to the World Obesity Federation’s World Obesity Atlas 2024. By 2035, if current trends continue, half of the world’s adults may be obese, with the projected annual global economic impact exceeding $4 trillion.

根据世界肥胖联合会的《2024年世界肥胖地图集》，肥胖已成为全球流行病，影响约10亿人。到2035年，如果目前的趋势继续下去，世界上一半的成年人可能会肥胖，预计每年全球经济影响将超过4万亿美元。

In addition to Wave, Regeneron and Alnylam are looking to tap into this market by silencing or knocking down specific genes to protect against obesity. Elsewhere, researchers at the University of Barcelona are developing an ex vivo gene therapy approach. No such products have made it to human testing yet, but the players in the field say they’ve got a real shot at providing results comparable to or even better than the GLP-1 agonists now flooding the market..

除Wave外，Regeneron和Alnylam还希望通过沉默或敲除特定基因来防止肥胖，从而进入这一市场。在其他地方，巴塞罗那大学的研究人员正在开发一种离体基因治疗方法。目前还没有这样的产品进入人体测试，但该领域的参与者表示，他们已经有机会提供与目前市场上充斥的GLP-1激动剂相当甚至更好的结果。。

Genetic Obesity Targets

遗传性肥胖目标

GLP-1 agonists are proving effective at reducing weight in a number of patients. For example, a review of 76 trials and more than 39,000 people shows significant improvements in blood glucose levels as well as weight loss ranging from 16 to 30 lbs in individuals with type 2 diabetes. Another study in non-diabetic individuals also reports substantial weight loss.

事实证明，GLP-1激动剂可有效减轻许多患者的体重。。另一项针对非糖尿病患者的研究也报道了体重大幅减轻。

This weight loss, however, comes at the expense of muscle loss, which can have serious consequences, particularly for elderly patients..

然而，这种体重减轻是以肌肉损失为代价的，这可能会产生严重后果，尤其是对老年患者而言。。

In a recent mouse study from Wave, a N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) successfully knocked down the INHBE gene to reduce fat while preserving muscle. “The mice lost no muscle mass but had a 56% reduction in visceral fat,” Bolno told BioSpace.

在Wave最近的一项小鼠研究中，N-乙酰半乳糖胺（GalNAc）偶联的小干扰RNA（siRNA）成功敲除了INHBE基因，以减少脂肪，同时保留肌肉。Bolno告诉BioSpace：“这些小鼠没有失去肌肉质量，但内脏脂肪减少了56%。”。

Wave researchers also looked at people whose whole genomes had been sequenced and stored in the UK Biobank, identifying individuals with loss of function variants. These people, Bolno said, exhibited “a low waist-to-hip ratio, low visceral fat, low levels of low-density lipoprotein (LDL) cholesterol and triglycerides,” suggesting that INHBE gene silencing in humans might induce “weight loss similar to semaglutide.”  .

Wave研究人员还观察了那些全基因组已测序并保存在英国生物库中的人，以确定功能丧失变异的个体。Bolno说，这些人表现出“低腰臀比，低内脏脂肪，低密度脂蛋白（LDL）胆固醇和甘油三酯水平”，这表明人类INHBE基因沉默可能导致“类似于semaglutide的体重减轻”。

Wave plans to launch clinical trials in 2025 with healthy, overweight patients. If those are successful, the study may be repeated with obese patients. Based on results to date, Bolno speculated that once- or twice-yearly treatment may be possible.

Wave计划在2025年对健康超重患者进行临床试验。如果这些成功，肥胖患者可能会重复这项研究。根据迄今为止的结果，博尔诺推测每年一次或两次治疗可能是可能的。

Of course, INHBE isn’t the only gene associated with obesity. Genome-wide association studies have identified approximately 250 such genes. The involvement of so many genes creates a plethora of potential targets.

当然，INHBE并不是唯一与肥胖相关的基因。全基因组关联研究已经确定了大约250个这样的基因。如此多基因的参与创造了大量潜在的靶标。

Regeneron is focusing on rare genetic mutations in the GPR75 gene that disable it and thereby protect against obesity. A 650,000-person study, which included data from the UK Biobank, identified those loss of function mutations in 1 of every 3,000 people studied. In that study, people with one or more inactive copies of the GPR75 gene weighed an average of 12 pounds less and had a 54% lower risk of obesity than those without the mutation..

Regeneron专注于GPR75基因中罕见的基因突变，这些突变使GPR75基因失效，从而防止肥胖。一项650000人的研究（包括英国生物库的数据）确定了每3000人中就有1人的功能丧失突变。在那项研究中，GPR75基因有一个或多个非活性拷贝的人平均体重比没有突变的人轻12磅，肥胖风险降低54%。。

Regeneron has three programs underway to target GPR75: a siRNA collaboration with Alnylam, a small molecule approach with AstraZeneca and an in-house antibody approach.

。

Meanwhile, researchers at the University of Barcelona are investigating ex vivo gene therapy as a way to create, and then implant, cells that produce the CPT1AM protein, which regulates fatty acid oxidation in the mitochondria. Their goal is to increase the body’s ability to burn fat.

与此同时，巴塞罗那大学（University of Barcelona）的研究人员正在研究离体基因疗法，以创建并植入产生CPT1AM蛋白的细胞，CPT1AM蛋白调节线粒体中的脂肪酸氧化。他们的目标是提高身体燃烧脂肪的能力。

Working with obese mice, senior researcher Laura Herrero reported significant reductions in weight, fatty liver, cholesterol and glucose levels. She and her team are now working to optimize the approach before moving into human testing.

高级研究员劳拉·埃雷罗（LauraHerrero）在研究肥胖小鼠时报告称，体重、脂肪肝、胆固醇和血糖水平显著降低。在进入人体测试之前，她和她的团队正在努力优化该方法。

The Outlook for Gene-Based Weight Loss Therapies

基于基因的减肥疗法的前景

Ending obesity isn’t as straightforward as silencing one or two genes. Most cases of obesity involve several different genes and are also related to epigenetics. For instance, endocrine disruptors, high-energy foods and a sedentary lifestyle can all contribute to obesity.

结束肥胖并不像沉默一个或两个基因那么简单。大多数肥胖病例涉及几种不同的基因，也与表观遗传学有关。例如，内分泌干扰物，高能量食物和久坐的生活方式都可能导致肥胖。

“If there is a mutation in a single gene causing the obesity—and there are cases, such as leptin or MC4R deficiency—then gene therapy and gene editing is, in principle, possible,” Giles S.H. Yeo, a professor of molecular neuroendocrinology at the University of Cambridge, told BioSpace in an email.

剑桥大学分子神经内分泌学教授Giles S.H.Yeo在一封电子邮件中告诉BioSpace：“如果一个基因突变导致肥胖，并且存在瘦素或MC4R缺乏症等病例，那么原则上可以进行基因治疗和基因编辑。”。

“The issue with polygenic obesity is that, first, it involves more than a thousand loci,” Yeo continued. “Second, most of the changes are non-coding, so determining which is the causative polymorphism is tough. Finally, the technology we have today does not allow us to target more than one or two genes or gene products.”.

Yeo继续说：“多基因肥胖的问题是，首先，它涉及1000多个基因座。”。“其次，大多数变化都是非编码的，因此很难确定哪种是致病多态性。最后，我们今天的技术不允许我们针对一个或两个以上的基因或基因产物。”。

For that reason, gene therapy won’t be a solution for every obese person. It is most likely for cases caused by a single gene or gene variant. For those, gene therapy . . . “might be considered as a last resort in patients who are not suitable for pharmacotherapy, and in whom other treatment approaches have failed,” Anke Hinney of the University of Duisburg-Essen, in Germany, and colleagues wrote in Nature Reviews Endocrinology..

因此，基因治疗并不是每个肥胖者的解决方案。最有可能是由单个基因或基因变异引起的病例。对于那些人来说，基因治疗。德国杜伊斯堡-埃森大学的安克·辛尼（Anke Hinney）及其同事在《自然评论内分泌学》（Nature Reviews Endocrinology）中写道：“可能被认为是不适合药物治疗且其他治疗方法失败的患者的最后手段。”。。

Additionally, developing gene therapy for obesity is more than a scientific challenge, of course. “High costs, potential unintended genetic consequences and ethical concerns around genomic editing must also be addressed,” Aaron Erez, a board-certified, private-practice physician specializing in functional medicine, told BioSpace via email..

。“还必须解决基因组编辑的高成本，潜在的意外遗传后果和道德问题，”Aaron Erez，一位专门从事功能医学的董事会认证私人执业医师，通过电子邮件告诉BioSpace。。

Yeo suggested that targeting the central nervous system with other therapies—GLP-1 agonists, for instance—may be a better approach. The reason, he explained in a 2021 paper in Nature, is that aspects of the central nervous system “control the hedonic aspects of food intake that are major drivers of obesity.” And, as he told BioSpace, “all of the current class of GLP-1-based anti-obesity therapeutics do, indeed, target the brain for their weight-loss effects.”.

Yeo建议用其他疗法（例如GLP-1激动剂）靶向中枢神经系统可能是一种更好的方法。他在《自然》杂志2021年的一篇论文中解释说，原因是中枢神经系统的各个方面“控制着食物摄入的享乐方面，这些方面是肥胖的主要驱动因素。”并且，正如他告诉BioSpace的那样，“目前所有基于GLP-1的抗肥胖疗法确实针对大脑的减肥效果。”。

Nonetheless, research studying the possible efficacy of gene therapies that target obesity “lay[s] the groundwork for tackling multifactorial diseases,” Erez said, “and could pave the way for more effective interventions.”

尽管如此，研究针对肥胖的基因疗法的可能功效的研究“为解决多因素疾病奠定了基础”，Erez说，“并可能为更有效的干预铺平道路。”

Gail Dutton is a veteran biopharmaceutical reporter, covering the industry from Washington state. You can contact her at gaildutton@gmail.com and see more of her work on Muckrack.

盖尔·达顿是一位资深的生物制药记者，从华盛顿州报道该行业。你可以联系她gaildutton@gmail.com更多关于黑幕的作品。