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bioRxiv · 10.1101/2024.12.30.630715

CCT-217: A Landmark Gene Silencing Therapeutic for Weight Loss That Enhances Lean Mass Composition, Reduces Visceral, Subcutaneous Fat and Restores Metabolic Health in Obesity through Browning

Reddy, R.·Singh, I.
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Abstract

According to the CDC, between 2017 and March 2020, 41.9% of U.S. adults aged 20 and older had obesity, with 9.2% experiencing severe obesity, affecting over 100 million and 22 million adults, respectively. Obesity prevalence increased from 30.5% in 1999-2000 to 41.9% in 2017-2020, while severe obesity rose from 4.7% to 9.2%. As per CDC projection, by 2030, nearly half of the US adults will be obese, with a quarter of them being severely obese. Current therapeutic approaches predominantly focus on appetite suppression and caloric restriction. This approach results in both fat mass and lean mass loss and thus compromises long term metabolic health. Preserving lean mass during weight loss is crucial. Remodeling of the white fat into beige fat through the process called browning offers a promising alternative to appetite suppression dependent weight loss, and complements with reduction of visceral fat, marrow adipose tissue, improve liver steatosis, enhancing insulin sensitivity, reduced cardiovascular risk and suppression of inflammation. Here, we present CCT-217, a groundbreaking siRNA therapy targeting CB1R and ZFP423 genes, with strong adipose tissue-specific tropism with nil brain and liver penetration in diet-induced obese (DIO) C57BL/6J male mice model (n=7 control, n=5 treated). Mice received 7 subcutaneous doses over 20 days (initial half-dose, followed by once after three days CB1R siRNA 2.0 mg/kg and ZFP423 siRNA 1.8 mg/kg dose). CCT-217 induced browning of the WAT and resulted in a significant 26% reduction in body weight with a modest 12% decrease in feed intake after the 4th dose, preserved normal clinical behavior and nutrition. Lean mass composition significantly improved to 79% versus 62% in controls, while total fat mass decreased by 43.5%. Notably, visceral fat depots, including retroperitoneal (59.4%), mesenteric (54.3%), and gonadal (42.0%) fat showed substantial reductions, alongside a reduction of 61.7% inguinal white adipose tissue (iWAT). Histological analysis revealed extensive browning of iWAT, reduced adipocyte size, and increased adipocyte count, indicating enhanced thermogenesis and adipose tissue remodeling. Liver pathology showed significant improvement, with reduced hepatocellular adipose vacuolation and the absence of fibrosis, inflammation, or macrophage infiltration, highlighting the hepatoprotective effects of CCT-217. Metabolic markers demonstrated a 20% reduction in plasma cholesterol and decreased systemic inflammation (21% reduction in CRP), accompanied by significantly improved leptin sensitivity and favorable trends in insulin sensitivity. Mechanistically, CCT-217 achieved 42-fold silencing of CB1R and 14.5-fold silencing of ZFP423 specifically in iWAT, with no off-target effects observed in liver or brain. In conclusion, CCT-217 emerges as a landmark therapy that effectively reduces visceral fat, enhances lean mass composition, and restores metabolic health through precise, tissue-specific gene silencing. These findings position CCT-217 as a transformative and highly promising next generation therapeutic for addressing obesity and its associated complications.

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Reddy, R., Singh, I.. 2024-12-30. CCT-217: A Landmark Gene Silencing Therapeutic for Weight Loss That Enhances Lean Mass Composition, Reduces Visceral, Subcutaneous Fat and Restores Metabolic Health in Obesity through Browning. https://doi.org/10.1101/2024.12.30.630715

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