Gleevec Cancer Drug Reported To Work In Alzheimer’s disease also working in Niemann Pick Type C mouse

A New York Times story is reporting that Paul Greengard (and his dog Alpha), who won a Nobel Prize for his work on signaling in brain cells, has found that the cancer drug Gleevec, is a new potential drug target for Alzheimer’s disease and blocks gamma secretase activating protein. Rudolph Tanzi and Paul Aisen are quoted in the article.

I think they would all be very interested to know that Gleevec is also working in Niemann Pick Type C mice and kids afflicted with this ultra rare condition are doing small personal trials with the drug.

Niemann Pick Type C disease is an ultra rare and fatal genetic cholesterol disorder caused by a double mutation on the NPC1 or NPC2 gene.  The disease is progressive neurological condition that causes dementia in children and is often referred to as the “childhood Alzheimer’s.”

Last year, in a comprehensive  drug screen conducted by Dr. Christopher Austin’s group at the National Chemical Genomics Center (NCGC), Gleevec showed up as a drug target for Niemann Pick Type C disease.

Dr. Brian Druker, an oncologist who revolutionized the treatment of cancer through research to develop Gleevec, is working with The Hadley Family in Medford, Oregon, who have two children suffering from Niemann Pick Type C disease. Novartis has offered to sponsor Gleevec for both of their children for a six month trial which is now underway. Children suffering from Niemann Pick Type C disease in Brazil are also taking Gleevec without any side effects.

Gleevec (also called Imatinib) has been studied by Dr. Silvana Zanlungo and Dr. Alejandra Alvarez of the Pontifica Universidad Catolica de Chile, and the results of their studies have indicated positive benefits in weight gain, strength and coordination in Niemann Pick Type C mice.  See the abstract: http://www.fasebj.org/cgi/content/full/22/10/3617 .  But only a very small amount of Gleevec crosses the blood brain barrier when given orally.  Imagine if you can do intrathecal?

There is also some evidence in the literature showing Imatinib effects on insulin resistance.  My twins have hypometabolism spreading throughout their brains and their PET scans show the pattern is very similar to early onset Alzheimer’s.

The Chile group has explored the relationship between Niemann Pick Type C neurodegeneration and the activation of the apoptotic system c-Abl/p73.  This system is formed by the c-Abl tyrosine kinase and p73 pro-apoptotic transcription factor. Both c-Abl and p73 proteins are expressed in the cerebellum, the brain region that is most affected in Niemann Pick Type C.

The Hadley’s have been leading the charge on getting Gleevec studies underway in Niemann Pick Type C mice. They have also been looking at Nilotinib, a tyrosine kinase inhibitor used for treatment of leukemia and other cancers.  However, Imatinib (Gleevec) I believe is working better in the mouse studies.

More and more scientific reports are coming out showing the relationship between Alzheimer’s disease and Niemann Pick Type C disease so I am not surprised that Gleevec could be a drug target in both conditions.

Dr. Kaj Blennow, a leading Alzheimer’s research in Sweden, has found Amyloid beta release is increased in Niemann Pick Type C. They are working on studies around γ-secretase and β-secretase and have found some data showing lipid accumulation affects Aβ metabolism. Amyloid metabolism in Niemann Pick Type C may be caused either by the impaired vesicular trafficking in NPC or by direct modulation by lipid alterations on amyloid processing enzymes (ie. gamma-secretase).

Another recent study by Alzheimer’s researcher Katarina Kågedal shows increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer’s disease.  The study measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and it was found that NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals.

Further, Ralph Nixon’s work shows that Alzheimer’s might have a lysosomal storage component like Niemann Pick Type C disease.

Intrathecal Gleevec – this is an interesting idea!  Since we are pursuing intrathecal cyclodextrin treatment on the twins, intrathecal Gleevec treatment might also be another potential avenue we could explore.