Vanda Pharmaceuticals Inc. announced the publication of an article entitled "Potential ASO-based personalized treatment for Charcot-Marie-Tooth disease type 2S" in Molecular Therapy Nucleic Acids1, a Cell Press partner journal, that describes the development of a novel antisense oligonucleotide (ASO) therapeutic, VCA-894A, for a patient with a rare variant in the IGHMBP2 gene causing Charcot-Marie-ToOTH disease Type 2S (CMT2S). In 1886, Jean-Martin Charcot, Pierre Marie, and Henry Tooth independently described this hereditary motor and sensory neuropathy in their patients, paving the way for Charcot-Marie- Tooth (CMT) disease research. It was not until 1968 that a distinction was made in CMT disease, creating the classification of CMT1 and CMT2.4 Since then, CMT disease has been used as a model disease to describe genetic heterogeneity.5 However, the high genetic and allelic heterogeneity of CMT disease poses a challenge for both diagnosis and treatment.
VCA-894A is being developed for a patient who was first diagnosed at the age of 5 with a rare subtype of CMT disease known as CMT2S. CMT2S is an inherited neuromuscular disorder that progressively leads to muscle weakness and loss of motor function, and has an estimated prevalence of less than 1 in 1,000,000 worldwide. The severity and clinical presentations of CMT2S are influenced by the diverse genetic variants associated with CMT disease, emphasizing the importance of principal and modifying genes in human diseases.
VCA-894 A targets a patient-specific IGHMBP2 variant and restores expression levels of IGHMBP2, highlighting the potential of this approach for personalized therapeutics for rare diseases. The article1 published discusses the development of this novel breakthrough therapeutic customized to a specific genetic mutation of a patient with CMT2S. The effects of VCA-894A were confirmed in Hesperos' Human-on-a-Chip neuromuscular junction model with patient-derived cells where VCA-894A demonstrated significant improvements in neuromuscular function, including reduced muscle fatigue and improved synaptic transmission between motor neurons and skeletal muscle myotubes.
The use of a microphysiological system to evaluate the effects of a genetically tailored treatment represents a significant advancement in precision medicine and the use of human relevant methods of evaluation. VCA-894 a has been granted an orphan designation by the FDA and it is expected to soon be administered to the specific patient for whom it was developed. The experimental platform described in today's article has the potential to unlock the development of treatments that can address significantly unmet medical needs based on genetic understandings and precision medicine.
