Pipeline & Programs

ACTX-401 in IGHMBP2-related disorders

ACTX-401 is an AAV9-delivered gene replacement therapy for the treatment of a rare form of Spinal Muscular Atrophy (SMA) called SMA with Respiratory Distress type 1 (SMARD1), and for Charcot-Marie-Tooth type 2S (CMT2S).

Also referred to as SMARD, Distal Spinal Muscular Atrophy 1 (DSMA1), or distal Hereditary Motor Neuropathy Type VI (dHMN6), SMARD1 is a severe neuromuscular condition in which spinal cord lower motor neurons degenerate, leading to motor function loss, particularly loss of respiratory function. Symptoms of SMARD1 are typically apparent within the first year of an infant’s life. There is presently no cure for SMARD1, and standard treatment addresses symptoms through mechanical ventilation and physical therapy. While SMARD1 is often lethal within the first year of life, a number of individuals have survived later into childhood or even into adulthood and are wheelchair and ventilator-dependent.

CMT2S is typically characterized with progressive motor and sensory polyneuropathy. It is clinically variable in its age of onset and level of severity. Even though most patients with CMT2S do not present respiratory symptoms initially, there are some reports in literature of patients presenting late onset respiratory failure leading to sudden death without previous diaphragmatic involvement.

SMARD1 and CMT2S are autosomal recessive genetic disorders caused by mutations in the gene that produces immunoglobulin mu-binding protein 2 (IGHMBP2) and are part of a larger family of disorders called IGHMBP2-related disorders (IRDs). ACTX-401 delivers a functional copy of the IGHMBP2 gene to patients, restoring expression of functional IGHMBP2. ACTX-401 clinical success in SMARD1 and CMT2S could lead to applicability to other IRDs in the future.