动物造模,神经元疾病 zi-bio 2024-02-26 832

　　On January 23, 2024, Vanda Biopharmaceuticals (VNDA) announced that its antisense nucleotide (ASO) drug VCA-894A targeting the IGHMBP2 gene has officially received FDA approval for a new drug clinical trial (IND). This marks VCA-894A as another clinically approved innovative therapy for IGHMBP2, following Alcyone Therapeutics' AAV9-IGHMBP2 gene replacement therapy. VCA-894A is a novel ASO that specifically targets recessive splicing site mutations in the IGHMBP2 gene, which can lead to the loss of motor neurons and degradation of the peripheral nervous system, resulting in a rare disease called Peroneal muscular atrophy type 2S (CMT2S), which was first defined in 2014. At present, the clinical trial stage treatment methods for IGHMBP2 have covered gene therapy and small nucleic acid drugs, and other therapies such as stem cell transplantation are also actively being developed [4-7].

　　The structure and function of IGHMBP2

　　Immunoglobulin helicase μ Binding protein 2 (IGHMBP2) is an ATP dependent DNA/RNA helicase, also known as cardiac transcription factor 1 (CATF1). It has multiple domains, including the DNA/RNA helicase domain, R3H single stranded nucleic acid binding domain, and zinc finger domain. IGHMBP2 belongs to the AAA+ATPase superfamily and can attach to specific regions of DNA, temporarily uncoupling the double helix of DNA [8]. Therefore, IGHMBP2 plays a regulatory role in DNA replication, repair, and transcription, as well as RNA metabolism and splicing, and protein translation, playing a crucial role in motor neuron survival, nervous system development and maintenance, and normal cardiac function maintenance.

　　IGHMBP2 mutation leads to CMT2S and SMARD1

　　Mutations in the IGHMBP2 gene can lead to significant differences in clinical phenotypes between spinal muscular atrophy with respiratory distress type 1 (SMARD1) and peroneal muscular atrophy type 2S (CMT2S). SMARD1 mainly affects the anterior horn of the spinal cord α- Motor neurons, characterized by early onset of muscle weakness and respiratory distress in infants, typically manifest in the first few months after birth, including muscle weakness in the diaphragm and other respiratory muscles, weakened reflexes, difficulty swallowing, and motor disorders. SMARD1 has a rapid onset and progression, which can easily lead to peripheral respiratory failure and endanger life [9].

　　In contrast, CMT2S is a hereditary neurological disorder that affects the peripheral nervous system and is a subtype of peroneal muscular atrophy (CMT). The incidence rate of CMT2S is less than 1/1000000, mainly in the first ten years of life. It is characterized by muscle weakness and atrophy of the distal extremities, sensory loss, and weakening or disappearance of tendon reflex [10-11]. Compared to SMARD1, the phenotype of CMT2S is lighter, usually not fatal, and generally not fatal