Novel therapies for genetic disorders

15 October 2008

The US Food and Drug Administration (FDA) has recently licensed for marketing, a new therapy for use in the routine prophylaxis of Hereditary Angioedema attacks (see press release). Hereditary Angioedema (HAE) is a rare genetic disorder, which results in deficiencies in a plasma protein known as C-1-inhibitor. This protein is involved in regulating clotting and inflammatory responses, consequently, deficiencies can lead to excessive tissue swelling. HAE is an autosomally inherited disorder that affects approximately 1 in 50, 000 people, although in some cases it can occur spontaneously as a result of mutations in the C-1-inhibitor gene.

A HAE attack occurs spontaneously and can be caused by stress, surgery or infection and results in rapid swelling of the hands, feet, limbs, face, intestinal tract or airway which is potentially fatal. Current treatment regimes in the US and UK for HAE attacks involve the use of steroid drugs in order to control the swelling. However, these can have adverse effects is some cases, such as liver toxicity and carcinogenicity. This new drug - Cinryze™ is a C1-esterase inhibitor product derived from human plasma. It has been approved on the basis that in clinical trials it was effective in preventing or decreasing the frequency of attack in most HAE patients and had side effects that were considered mild or moderate.

A potentially more widely useful therapeutic for selected genetic diseases is currently in development; US-based PTC Therapeutics’ PTC124 is a candidate drug in phase 2a clinical trials (seeking to demonstrate proof of clinical benefit in patients). PTC124 suppresses the effect of a particular type of mutation, nonsense mutations, which normally cause premature termination of proteins. By allowing the cellular transcription process to continue past the nonsense mutation, PTC124 has been shown to allow the production of functional CTFR protein in cystic fibrosis patients with nonsense mutations in the CTFR gene, and of functional dystrophin protein in Duchenne Muscular Dystrophy (DMD) patients with nonsense mutations in the dystrophin gene. If the drug is proven to confer clinical benefits in such patients, it could potentially be appropriate for the treatment of around 15% of all patients with genetic diseases, as this type of mutation is quite a common one.

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