ATC Group: M09AX Other drugs for disorders of the musculo-skeletal system

A nonsense mutation in DNA results in a premature stop codon within an mRNA. This premature stop codon in the mRNA causes disease by terminating translation before a full-length protein is generated. Ataluren enables ribosomal readthrough of mRNA containing such a premature stop codon, resulting in production of a full-length protein.

Autologous chondrocyte implantation (ACI) is based on the extraction of the patient’s own chondrocytes isolated from healthy cartilage, their culture in vitro and their subsequent implantation into the cartilage defect. The implantation suspension is cultured and implanted as three-dimensional spheroids.

Delandistrogene moxeparvovec is the recombinant gene therapy product that is comprised of a non-replicating, recombinant, adeno-associated virus (AAV) serotype rh74 (AAVrh74) capsid and a ssDNA expression cassette flanked by inverted terminal repeats (ITRs) derived from AAV2. The cassette contains: 1) an MHCK7 gene regulatory component comprising a creatine kinase 7 promoter and an α-myosin heavy chain enhancer, and 2) the DNA transgene encoding the engineered delandistrogene moxeparvovec micro-dystrophin protein.

Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping.

Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its effect in patients with Duchenne muscular dystrophy (DMD) is unknown.

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to an intronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleic acid (pre-mRNA) and hence when SMN2 mRNA is produced, it can be translated into the functional full length SMN protein. SMA is a progressive neuromuscular disease resulting from mutations in chromosome 5q in the SMN1 gene. Gene SMN2, located near SMN1, is responsible for a small amount of SMN protein production.

Onasemnogene abeparvovec is a gene therapy designed to introduce a functional copy of the survival motor neuron gene (SMN1) in the transduced cells to address the monogenic root cause of the disease. By providing an alternative source of SMN protein expression in motor neurons, it is expected to promote the survival and function of transduced motor neurons.

In patients with fibrodysplasia ossificans progressiva (FOP), abnormal bone formation, including heterotrophic ossification (HO), is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). Palovarotene is an orally bioavailable retinoic acid receptor agonist, with particular selectivity at the gamma subtype of RAR. Through binding to RARγ, palovarotene decreases the BMP/ALK2 downstream signaling pathway by inhibiting the phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation.

Risdiplam is a survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier designed to treat SMA caused by mutations of the SMN1 gene in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is directly linked to the SMA pathophysiology which includes progressive loss of motor neurons and muscle weakness. Risdiplam treats SMA by increasing and sustaining functional SMN protein levels.