Management of Rare Diseases

Many rare disease treatments are at the cutting edge of therapeutic advances.

Cystic Fibrosis

There are four CFTR (cystic fibrosis transmembrane regulator) modulator drugs available. Each targeting only a proportion of CF patients. For example, Ivacaftor (Kalydeco) targets primarily the G551D mutation, patients with this mutation account for approximately 5% of CF cases. CFTR modulators work by potentiating the channel-open probability (or gating) of the CFTR protein and enabling increased chloride transport.

Duchenne Muscular dystrophy (DMD)

The DMD gene is the largest in the human genome with 79 exons, which encodes the huge dystrophin protein. In DMD a pathogenic variant leads to a premature stop codon and a truncated protein.

Ataluren (Translarna) is a licensed therapy available under a managed access scheme in England for patients with DMD. It is a ‘Stop-codon read through’ therapeutic. It makes the Ribosome less sensitive to incorrect stop codons, thereby reading through these to make more of the full length and better functioning dystrophin protein. ‘Exon Skipping’ therapies are another DMD new therapy, with one approved (Eteplirsen) and two in phase 3 trial for DMD. Exon skipping therapies, as the name suggests skip the exon with the error, enabling a longer although not full-length dystrophin protein to be formed. As the exon-skipping drugs are designed to skip over a particular exon, different versions are needed depending on which exon should be skipped. The approved therapy eteplirsen skips exon 51 (mutation in exon 51 accounts for 13% of DMD cases).

Gene Therapy

Although there are more than 800 ongoing gene therapy trials, there are currently only 4 licensed gene therapy treatments for familial lipoprotein lipase deficiency, rare inherited retinopathy, Spinal Muscular atrophy (SMA), and recurrent melanoma.

The article linked in the further reading section is a review of recent advantages in gene therapy. You may have institutional access to the review by Cring & Sheffield.

How do you think advances in genetics will change the management of rare diseases in the next few years?