Mutation-specific treatment options

Question

Dear expert team,

my son is heterozygous IVS8-2A>C (intron 8) and F508del (exon 10). According to the CF clinic, he has had a mild course of the disease and is in very good shape. Which therapy forms (mutation-specific) are options for this very rare heterozygosity?

I assume research mainly focuses on more common mutations?

Many thanks for your answer!

Answer

Hello,

your son thus has one frequent (c.1521_1523delCTT = p.Phe508del = F508del) and one very rare (c.1210-2A>C = 1342-2A>C = IVS8-2A>C) mutation. First of all, one has to say that the different nomenclatures are quite confusing.

It is known that the 1800+ mutations can be categorized into different classes. These classes provide information on the function of the chloride channel (CFTR), which is defective in cystic fibrosis. Class I (protein is not produced) and class II (protein is folded wrongly), class III (defective regulation), class IV (tight channel), class V (not enough channels) or class VI (decomposition happening too fast) mutations are associated with different chloride channel activity and disease severity.

It is particularly important to mention that CFTR mutations often have manifold characteristics and can therefore be assigned to more than one class. Nevertheless, it is still not possible to give an exact prognosis based on the mutation. Apparently, other factors such as other genes (modifying genes), the environment and – mathematically speaking – “stochastics” play a significant role as well.

Now concerning your question: of course, researchers attach great importance to exploring new drugs for the therapy of the common mutations. F508del, for example, one of your son’s mutations, is at the centre of current research. Due to its class, the mutation is a potential point of action for new drugs, so-called correctors, which help build the chloride channel into the cell membrane. New drugs or agents such as VX-809 or VX-661 are one subject of current research. One drug which belongs to the group of potentiators, i.e. it positively influences the function of the channel that has already been built into the cell membrane, has already been approved in the United States. Apart from a normalization of the sweat test, this drug (VX-770, also called ivacaftor (generic name) or Kalydeco® (brand name)) has also shown improvements in lung function and an increase in body weight. In Germany, however, it is only approved for a very rare mutation (G551D, ca. 3% of patients in Germany). I can therefore confirm that patients with very rare mutations do benefit as well from current research.

Unfortunately, I am unable to categorize your son’s other mutation, IVS8-2A>C, into any of these mutation classes, even though the working group around Prof. Tümmler in Hannover has described it (*1). It is known, though, that this is a severe splice mutation. I am not aware of any new developments concerning mutation-specific therapies for this mutation which occurs at obligatory conserved splice points.

Kind regards
Dr. Olaf Eickmeier


*1. Dork, T., Fislage, R., Rappen, U. & Tummler, B. Severe splice site mutation preceding exon 9 of the CFTR gene. Hum Mol Genet 2, 1313-1314 (1993).

05.06.2012