Genes encased in adeno-associated virus (AAV) delivery vehicles are injected into muscle. From there they can travel through the nerve fiber to the nervous system.
In a recently completed clinical trial for insulin-like growth factor 1 (IGF1) in ALS, (see “Third IGF1 trial” ), investigators found the protein did not slow the progression of weakness, prolong survival or slow functional deterioration in people with ALS.
In spite of these results, IGF1 may yet have a future in treating ALS.
Studies in the 1990s showed conflicting results
The naturally occurring protein IGF1 plays an important role in human growth and development. It also belongs to a group of chemicals called “neurotrophic factors,” which contribute to the growth and survival of neurons (nerve cells).
As a potential therapy, IGF1 was developed under the brand name Myotrophin by the pharmaceutical company Cephalon of Frazer, Pa., and its partner Chiron of Emeryville, Calif.
Two human clinical trials of Myotrophin, delivered by subcutaneous (under the skin) injection in ALS patients in the 1990s, demonstrated inconclusive results. The first study, in North America, suggested a beneficial effect as measured by the Appel ALS rating scale, which measures loss of function over time. A large European study, however, failed to demonstrate benefit; in addition, more deaths occurred among patients who received the drug than in those who received a placebo.
“We were left with one ‘good’ study and one ‘failed’ study — with the latter possibly due to unequal baseline stratification of patients — and a third study was truly needed,” said neurologist Stanley Appel, director of MDA’s ALS Center at the Methodist Neurological Institute in Houston (and creator of the Appel ALS rating scale).
Results from ‘tie-breaker’ trial negative
Cephalon provided the drug for the recent third and “tie-breaking” trial, in which IGF1 again showed no benefit in people with ALS.
Appel noted the protein still may have potential if administered differently, such as by viral-vector or stem cell delivery, but, he said, “This trial settles the question as to whether injection of IGF1 in this form has a significant clinical benefit.”
Down, but perhaps not out
The possibility that IGF1 may yet provide some benefit in ALS might depend on tweaking the protein’s structure or changing the method of delivery.
One structural variation of IGF1 that has garnered a significant amount of interest is Iplex, a combination of IGF1 and binding protein 3 manufactured by Insmed of Richmond, Va. (In the body, IGF1 connects to binding proteins that prolong its usefulness and help deliver it to target tissues.) Iplex, like IGF1, is administered via subcutaneous injection.
Although it’s being studied in myotonic muscular dystrophy, Iplex never has been rigorously tested in ALS, and there currently is no evidence to support its use in ALS.
Delivery as gene therapy
Another possible IGF1 approach that may yield greater success in reaching the nervous system (brain and spinal cord) is gene therapy.
One proposed method involves encasing genes for IGF1 in adeno-associated viral (AAV) delivery vehicles and injecting them into muscle, from which they can travel to the nervous system.
In 2003, Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore, and colleagues, demonstrated the feasibility and benefit of this strategy in animals. Mice with an ALS-like disease survived a median 37 days longer than untreated animals with the same disease after IGF1 gene therapy.
Brian Kaspar at Nationwide Children’s Hospital in Columbus, Ohio, also has shown that AAV delivery of IGF1 to the spinal cord can lengthen survival in mice with a disease resembling ALS. Kaspar currently has MDA support to further develop IGF1 gene therapy.
The road ahead
The differences between injecting the IGF1 protein subcutaneously, as was done in the three IGF1 human clinical trials, and injecting a modified version of it or delivering it via gene therapy, may be the differences between failure and success for IGF1 in ALS.
The field has come a long way since Myotrophin was first developed. At that time, researchers believed the large protein molecule might somehow reach the ALS-affected nervous system (which it didn’t do) or that its positive effect on muscle fibers might maintain patients’ strength in the face of nerve-cell destruction (another false hope).
The last few years of research have shown that genes, which are far smaller than proteins, can be directed to muscle tissue and from there can travel to nerve cells. It’s also been learned, through studies of IGF1 in another disease, that attaching a second protein to IGF1 may allow its safe delivery in doses high enough to offer some protection to muscle cells, even in ALS.