Daria Lizneva, MD, PhD, leads a team of investigators at the Center for Translational Medicine and Pharmacology at the Icahn School of Medicine at Mount Sinai, which is an XSeed Award Finalist for its work on developing an innovative treatment for obesity. Their strategy involves activating the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) pathway in adipocytes (fat cells), using a medication that increases energy expenditure and reduces fat accumulation. Lizneva is an Associate Professor at the Center and the Director of the Reproductive Biology Group.
The XSeed Award provides critical funding to translate scientific discoveries into commercially successful drug therapies. The 2024 XSeed awards will provide two winning teams up to $250,000 for New York City minority- and women-led life science and healthcare startups working on novel drug development projects. The winners will be announced in September 2024.
Cure: How did you get involved in this area of research?
Daria Lizneva: As an obstetrician and gynecologist, I used to run a large clinic for women with polycystic ovary syndrome (PCOS), a reproductive disorder associated with multiple endocrine abnormalities, including altered secretion of luteinizing hormone (LH). Women with PCOS who are not ovulating often present with central obesity and a disturbed waist-to-hip ratio (WHR). I was interested in understanding how reproductive hormones, like LH, can influence body composition.
I joined Mount Sinai in 2017, where Dr. Mone Zaidi's lab was studying the effects of another fertility hormone — follicle-stimulating hormone (FSH) — on adipose tissue. He had published a Nature paper demonstrating that blocking FSH could induce leanness in mice, and I proposed we investigate the effects of LH. That's how this project got started. We found that LH induces leanness in mice, which corresponds to what we see in humans.
Cure: How does Org 43553, your novel small molecule, work?
Lizneva: We demonstrated that the LHCGR is located on adipocytes. Org 43553 is a small molecule that binds to the LHCGR. It activates this receptor on adipocytes, which increases energy expenditure and reduces fat accumulation. This is a novel mechanism of action that has never been described before. It was a very exciting finding!
Cure: What have you learned so far about the effectiveness of Org 43553 from your preclinical studies?
Lizneva: Our preliminary efficacy studies have shown that Org 43553 reduces total body fat in mice, despite equal food intake in both study groups. There was a shift in adipocyte size distribution, marked by a significant increase in smaller adipocytes in mice treated with Org 43553 in the visceral fat depot, which mimics data in humans with normal WHR parameters. The data suggest that LHCGR activation by Org 43553 induces a lean phenotype, with more profound action on visceral fat.
Cure: How does Org 43553 compare with glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide, which are so popular right now?
Lizneva: GLP-1 induces weight loss indirectly by increasing insulin secretion, inhibiting glucagon release, slowing gastric emptying and suppressing appetite. In contrast, Org 43553 acts directly on adipocytes, increasing energy expenditure and reducing fat accumulation. By targeting adipocytes directly, it offers more precise control over fat metabolism with the potential for fewer side effects. Additionally, drugs that work directly on adipocytes can complement other treatments that act indirectly, providing a multi-faceted approach to managing obesity.
GLP-1 medications do not address WHR, a major predictor of long-term mortality. Conditions characterized by altered LH secretion, such as menopause and PCOS, are associated with abnormal WHR. In addition, LH levels have been constantly linked to body composition outcomes in large epidemiologic cohorts. There is therefore an unmet need for obesity treatments targeting WHR. As an agonist of LHCGR, Org 43553 is a promising candidate for this purpose.
Cure: If you win the Cure XSeed Award, what would that mean for this project?
Lizneva: Obesity is a significant issue and is widely recognized as a major global health concern, affecting more than one billion people around the world. By 2030, nearly half of all adults in the United States are expected to be obese. While GLP-1 receptor agonists help with weight loss and glycemic control, no FDA-approved anti-obesity medications currently can modify WHR — the only valid predictor of long-term morbidity and mortality. Org 43553 is an interesting molecule that has an unusual and previously undescribed effect on body composition.
If we win the XSeed Award, it will help us facilitate and accelerate the preclinical development of Org 43553 to a phase 1 clinical trial. We also know that Org 43553 appears to be safe in humans, at least in the short term, because it was tested for infertility already and shown to be safe in a phase 1 clinical trial. So, we are quite confident that this drug can be used in people.
Cure: Who is on your team?
Lizneva: The leadership team includes co-inventors Mone Zaidi, Tony Yuen and me. Funding from the National Institutes of Health covers part of this work. Our research team consists of four investigators from the Center for Translational Medicine and Pharmacology in the Department of Pharmacological Sciences at Mount Sinai: Anisa Gumerova, MD, PhD, Assistant Professor; Ofer Moldavski, PhD, Instructor; Satish Rojekar, PhD, Postdoctoral Fellow; and Anusha Pallapati, PhD, Postdoctoral Fellow. We also benefit from support within the Department of Pharmacological Sciences, which is ranked third in the United States in pharmacology by the National Institutes of Health. In addition, we collaborate with industry advisors to facilitate drug development.