IGF-1 Does Look Promising – Part II

In Tuesday’s article, I discussed the research that Dr. Maria Pennuto and others are doing using IGF-1.  Today’s article is a small portion of the transcript of that chat with some additional explanations and definitions provided by me.  For those of us not very scientifically inclined, some of the explanations might be over our head.  Do not let that stop you, however, because there is the potential of a major breakthrough for our children and possibly for those just beginning to show the symptoms of Kennedy’s Disease.

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Q:  Could you bring us up to date on your IGF-1 research?

DRMP:  IGF-1 is a factor that promotes cell survival.  IGF-1 works by initiating a signal that modifies factors that are inside the cell. 

IGF-1 is outside the cells, but binds a factor on the cell’s surface.  After this event, a series of changes end up with activation of a factor named AKT.

Q:  What does AKT stand for and mean?

DRMP:  AKT is what we call kinase.  It is an enzyme that adds a phosphate group to specific sites in the protein.  [Kinases are used extensively to transmit signals and control complex processes in cells] The Androgen Receptor (AR) is a target modified by AKT.  So, IGF-1 activates AKT which in turn modifies the AR.

Q:  How does this modification influence SBMA (Kennedy’s Disease)?

DRMP:  We have shown that once modified by AKT, the AR is no longer able to bind testosterone.  This finding was surprising and very important for the disease because the disease is triggered by testosterone.  We have also shown that the AR modified by AKT gets degraded by the cell … it does not accumulate in the cell.  So, we decided to use this information to see if in the mouse model that IGF-AKT-AR signal could be used to attenuate (weaken, reduce severity) the disease. 

Q:  What is the difference between IGF-1 and IGF-1 for muscles?

DRMP:  That is a critical point.  In a cell, there are several types of IGF.  Some act systemically and are generated by the liver.  Muscle IGF is the form of IGF-1 used in our previous study.  We know that in principle the muscle-generated IGF works in the mouse model, but to use this approach in humans we need delivery via a virus.  Dr. Fischbeck at NIH is using IPLEX, which is another form of IGF already used in humans.  If this works, it is to our advantage. 

Q:  What is IPLEX?

DRMP:  IPLEX is binary protein complex of human insulin-like growth factor-1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3), both produced by recombinant DNA technology which means that is acting systemically.  [From Wikipedia:  Mecasermin rinfabate (trade name IPLEX) is a drug consisting of recombinant Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3).  It is a drug already approved for use by the FDA.]

Q:  In your research, when IGF-1 is started pre-symptom, the mouse had a later onset of Kennedy’s Disease and less severe progression of the disease.  Correct?

DRMP:  Yes, in our experiments, if IGF was there before disease onset our mouse models were producing more IGF afterwards.  It remains to be established if this can work in the mouse models being tested after disease onset.

Q:  You commented earlier that your original research was on pre-symptom Kennedy's Disease mice.  How about those of us that already have the symptoms? 

DRMP:  Yes, Dr. Fischbeck is now testing IGF-1 (IPLEX) on mice models already showing symptoms (just after disease onset) because patients are already symptomatic when diagnosed with Kennedy’s Disease.  Dr. Fischbeck wants to see if IGF-1 will slow the progression after the disease’s onset. 

Q:  And, what if IPLEX does not work?

DRMP:  We are also generating viruses expressing IGF-1 (muscle-generated) just in case IPLEX does not work.  Of course, these viruses have to be tested in mouse models first.  We have already discovered a huge effect of IGF on skeletal muscles in SBMA mice compared to the control group of mice.  What is also important is that intervention in muscle preserved motor neurons in the spinal cord, suggesting that if we can protect muscle we can also do something for the neurons and it can be easier to plan intervention for muscles than for the spinal cord.

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Again, this is just a short portion of the chat.  You can find the entire transcription at the KDA web site under Chat Transcripts.  Look for the March 06, 2010 chat transcript.

This is pretty exciting stuff.  Other research projects are also making headway in finding that elusive treatment for Kennedy’s Disease.  I find it encouraging that several of these projects are focusing on finding ways to allow the androgen receptor to do its job.  I do not know about you, but chemical castration just does not appeal to me (ouch!).

[Author's Note:  On March 13, I updated several sections above after conferring with Dr. Pennuto]