making muscle wasting history

The insulin-like growth factor (IGF-I) is a protein with about 70 amino acids in one chain with three stabilizing bridges, thus with a similar shape as insulin. It exists in multiple forms with slightly different structures. One of these so-called isoforms, IGF-1A, is very beneficial for muscle, because it helps to promote growth and strength and is of interest for a possible therapeutic use in Duchenne children. The research team of Prof. Elisabeth Barton of the University of Pennsylvania in Philadelphia works with mdx mice which were genetically engineered, so that they produce high levels of IGF-I in their muscles throughout their lifetime. These mdx-IGF-plus mice show an increased muscle growth with quite healthy-looking muscles and much less fibrosis than the “normal” mdx mice.

But because this growth factor interferes with many processes in other than muscle cells, potentially serious side effects cannot be excluded if higher dosages are used to optimize the effect on muscles. Therefore, IGF-I was complexed with one of its binding proteins (IGFBP3) to produce IPLEX™, an already approved drug that stabilizes IGF-1 in the blood, and releases it only where and when it is needed. A first clinical trial with IPLEX was performed at University of Rochester with 15 adult myotonic dystrophy patients. This strategy could be very effective in getting IGF-I to the muscle without causing side effects in other tissues.

Another way to create higher levels of IGF-I in muscle tissue would be to transfer its gene into muscles with AAV vectors, which would instruct them to make more IGF-I. Work with this technique in Dr. Barton’s laboratory succeeded in increasing the level of the most active isoform IGF-IA 30 to 40 fold after intramuscular injection of the vectors. The newly synthesized IGF-I stayed in the muscle tissue, promoted hypertrophy (enlargement of muscle fibers), but avoided side effects caused by the activation of non-muscular tissues. Such a viral gene therapy will take several years until it could be tried in Duchenne boys.