ACVR2A: A key target for muscle growth, weight Loss, and Pulmonary Arterial Hypertension (PAH) in drug research.

• Gene Information: ACVR2A encodes a receptor that mediates the functions of activins, which are members of the transforming growth factor-beta (TGF-beta) superfamily involved in diverse biological processes.
• Protein Expression: ACVR2A is ubiquitously expressed across normal human tissues—particularly in the cytoplasm and cell membrane—and plays a vital role in cellular differentiation, embryonic development, and bone mass regulation.
• Signaling Pathway: ActRIIA/ACVR2A and ActRIIB/ACVR2B are TGF-β superfamily transmembrane proteins that serve as type II receptors for activin A, driving essential processes in cellular growth, differentiation, and tissue regeneration.
• Therapeutic Method: Currently, several preclinical and clinical studies are exploring the effects of antagonists or agonists of ACVR2A and ACVR2B receptors in disease treatment.

ACVR2A

The exons 1-11 of the mouse Acvr2a gene that encode the whole molecule, including promoter, 5’UTR, and part 3’UTR, were replaced by the exons 1-11 of the human counterparts, including human promoter, 5’UTR, and human 3’UTR in B-hACVR2A mice. The human ACVR2A expression is driven by the human ACVR2A promoter, while the mouse Acvr2a gene transcription and translation will be disrupted.

Species specific analysis of ACVR2A mRNA expression in wild-type C57BL/6JNifdc mice and heterozygous humanized B-hACVR2A mice by RT-PCR. Gastrocnemius were collected from wild-type C57BL/6JNifdc mice (+/+) and heterozygous B-hACVR2A mice (H/+), then cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human ACVR2A primers. Human ACVR2A mRNA was detectable only in heterozygous B-hACVR2A mice, but not in wild-type C57BL/6JNifdc mice. Human sequences were confirmed via Sanger Sequencing.

• Mouse Acvr2a mRNA was detectable only in wild-type C57BL/6JNifdc mice.
• Human ACVR2A mRNA was detectable only in homozygous B-hACVR2A mice but not in wild-type mice.

Species specific analysis of ACVR2A mRNA expression in wild-type C57BL/6JNifdc mice and homozygous humanized B-hACVR2A mice by RT-qPCR. Gastrocnemius, brown fat, and inguinal fat were collected from wild-type C57BL/6JNifdc mice (+/+) (male and female, n=3, 8-week-old) and homozygous B-hACVR2A mice (H/H) (male and female, n=3, 8-week-old), then cDNA libraries were synthesized by reverse transcription, followed by RT-qPCR with mouse or human ACVR2A primers. Human ACVR2A mRNA was detectable only in homozygous B-hACVR2A mice, but not in wild-type C57BL/6JNifdc mice. Mouse Acvr2a mRNA was exclusively detectable in wild-type mice but not in B-hACVR2A mice. All results were normalized to the gastrocnemius muscle. Values are expressed as mean ± SEM.

• ACVR2A protein was detectable in homozygous B-hACVR2A mice and wild-type C57BL/6JNifdc mice, as the antibody cross-recognized both human and mouse ACVR2A.

Western blot analysis of ACVR2A protein expression in homozygous B-hACVR2A mice. Various tissue lysates were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hACVR2A mice (H/H) (male, 8-week-old), and then analyzed by western blot with anti-ACVR2A antibody (R&D, AF340). 40 μg total protein was loaded for western blot analysis. ACVR2A protein was detectable in homozygous B-hACVR2A mice and wild-type C57BL/6JNifdc mice, as the antibody cross-recognized both human and mouse ACVR2A.

The inhibitory efficiency of the nucleic acid drug against human ACVR2A in homozygous B-hACVR2A mice. B-hACVR2A mice (H/H) were randomly divided into two groups (female, 6-week-old, n=3). The human ACVR2A targeted nucleic acid drug and PBS were administered to the mice individually. The mice were sacrificed on day 21, and the inguinal subcutaneous fat, perigonadal fat, and quadriceps femoris tissues were collected to detect the expression level of human ACVR2A mRNA by qPCR. (A) The schematic diagram of experimental processing. (B) The expression of human ACVR2A mRNA was normalized to the PBS group of each tissue. Values are expressed as mean ± SEM. Significance was determined by two-way ANOVA, *P<0.05, **P<0.01, ***P<0.001.  

Note: This siRNA from a client targets ACVR2A in adipose and muscle. Data are shared upon the client's approval.

In Vivo Efficacy Study of hACVR2A-antibody drug in B-hACVR2A Mice. B-hACVR2A mice (6-week-old, male, n=6) were treated with DPBS or LAE-102-analog. Whole-body MRI was performed throughout the 28-day observation period to monitor body weight, absolute lean mass, and absolute fat mass over time.

Note: Data are shared upon the client's approval.

• LAE-102 (ACVR2A-antibody) specifically promotes lean mass growth without accelerating fat accumulation in lean B-hACVR2A mice.

In Vivo Efficacy Study of hACVR2A-antibody drug in B-hACVR2A Mice. B-hACVR2A mice (6-week-old, male, n=6) were treated with DPBS or LAE-102-analog. Whole-body MRI was performed throughout the 28-day observation period to monitor body weight, absolute lean mass, and absolute fat mass over time. (A) Body weight change after treatment. (B) Lean weight change after treatment. (C) Fat weight change after treatment. Note: Data are shared upon the client's approval.