Losartan: Hypertension Drug May Be the Answer to Marfan Syndrome!
The outline of this article is as follows:
What is Losartan?
What is Marfan syndrome (MFS)?
A list of symptoms.
The Molecular basis of this syndrome.
Traditional management of MFS.
The mouse-model for Marfan syndrome.
The impact of this discovery.
***What is Losartan?***
Losartan (Coozar) , approved by the FDA and USDA, made its appearance in 1995. It was meant to treat hypertension. It has been prescribed to diabetics and people suffering from kidney failure. This drug was developed by Merck. Losartan acts as an antagonist of a hormone that causes hypertension.
Hypertension can be brought about by angiotensin 1 (AT1) in one of two ways :
1) vasoconstriction
2) fluid retention due to increased sodium uptake.
The hormone angiotensin 1 can be prevented from having this effect in two ways. Drugs that lower hypertension by acting as angiotensin receptor blockers are known as ARBs. Drugs that block the angiotensin converting enzyme are known as ACE.
Losartan is an ARB.
***What is Marfan syndrome?***
First described in 1896, Marfan syndrome is a disease of the connective tissue. Antoine Marfan, a French pediatrician, was the first to recognize the set of symptoms that are typical of Marfan syndrome. It is characterized by long arms, elongated fingers, poor eyesight, and arterial hypertrophy, aortic aneurysms. Ninety five years later, the genetic basis for this disease was discovered. Marfan syndrome (MFS) is a disorder affecting the connective tissue and is caused by an autosomal mutation on chromosome 15.
***A list of symptoms***
Bone overgrowth, aortic aneurysm, dislocated lens, emphysema, hypertrophy and dysfunction of mitral valve tissue are some major symptoms associated with this disease.
The remarkable aspect of this disease is that unlike other diseases, there is no biochemical indicator present in the bloodstream. Hence, there is no way of detecting it unless mutational analysis is carried out. This mutation is seen in one in 3000-5000 people. (Considering all the above, Antoine Marfan did possess acute powers of observation because he was able deduce the existence of the disease based purely on physical symptoms. )
***Molecular basis of the syndrome***
Harry C.Dietz of Johns Hopkins , along with his team , discovered in 1991 that the molecular basis for this disease is mutations in a gene coding for a structural protein, (FBN1) fibrillin-1. However, Dr.Dietz was not convinced that this was the sole cause for the set of symptoms. Eventually, it was established that fibrillin-1 acts as a regulator of TGF-beta. The mutant form is no longer able to bind to TGF-beta. Hence the hypertrophy of the aortic tissue. Since it is an autosomal dominant mutation, all individuals with this mutation show the symptoms. The severity of the symptoms seems to vary from individual to individual.
***Traditional management of MFS***
Ninety percent of MFS patients develop changes in their aorta and heart. Aneurysms can be removed surgically and an aortic graft is introduced. Lens dislocation is also surgically corrected. A study published in 1995 in The American Journal of Cardiology indicated that the life-expectancy has increased by 25% since 1972. However, the number of surgeries the patients of MFS have to endure is higher. This is largely due to:
Better diagnosis of milder cases
Better surgical options.
Use of beta-blockers.
A general increase in the life expectancy
A synopsis of the sequence of events in MFS are as follows:
Normal human being fibrillin1 FBN-1
Binds to TGF beta.
Normal cardiovascular tissue growth
Normal valve function and aortic root
MFS: mutant form of fibrillin1 Fbn1
Cannot bind to TGF-beta.
Hypertrophy
Mitral valve prolapse, aortic anuerysm
***The mouse model for Marfan syndrome***
Dr.Dietz and his team started working with a mouse model for Marfan syndrome by knocking out the FBN1 gene.
Mice homozygous for Fbn1 showed two very clear-cut symptoms:
Impaired alveolar septation
Increased collagen deposits
Increased collagen deposits are indirectly indicate increased TGF-beta signaling.
What underscored the role of TGF-beta regulation in MFS is that antibodies raised against TGF_beta were injected into the blood stream of MFS affected mice, the symptoms were attenuated.
Armed with this mouse model that comes very close to showing symptoms of Marfan syndrome in human beings, the team tested the hypertension drug losartan. They found that the mice treated with the drug showed no signs of having been affected by Marfan syndrome and were indistinguishable from the wild type. Microscopic examination of the tissue from losartan treated “Marfan mice” showed that the fragmentation was reduced to the extent of tissue being indistinguishable from healthy mice tissue.
For images, please see:
http://www.hopkinsmedicine.org/Press_releases/2006/04_06_06.html
***The impact of this discovery***
The most life-threatening symptom of this syndrome is the aortic aneurysm. Often , surgery is employed to correct the aortic dilatation , hypertrophy and septal-dysfunctions, to name a few.
The impact of this discovery is that surgery can be avoided. Surgery is risky because in some cases it involves operating on small children. Also, beta-blockers that are generally prescribed patients only seem to slow the rate of growth. Hence the advantage of using Losartan is two fold: Losartan seems to not only eliminate surgery but prevent future occurrence of hypertrophy. This is thanks to Dr.Dietz suspecting that the symptoms of Marfan syndrome are not caused by the mutations in a structural gene. He felt there must be a distinct reason for the hypertrophy. This lead to his surmising that there is an up-regulation of TGF-beta. His team, in 2003, found that fibrillin-1 binds to TGF-beta, thus regulating this cytokine.
Due to the mutation, fibrillin-1 can no longer bind to TGF-beta. This leads to an unregulated amount of growth.
Losartan blocks TGF-beta, thus eliminating the hypertrophy, aortic anuerysms and aortic dissection that are characteristic of MFS. Since this drug has already met with approval from FDA and USDA, it can be prescribed to human beings with MFS in the near future.
Not only does this give more hope to people with MFS, but this study provides a new direction for studying genetic diseases.
This study excelled where most others failed because of the unique way in which the investigators attacked the problem.
They first developed a mouse model for MFS.
They then studied the pathway that goes awry in MFS. By targeting the parts of the metabolic pathways that are disrupted due to the mutation in MFS, they were able to find the perfect drug to treat the disease. (The interesting part of the study is the prenatal administration of the drug. )
This elegant study is bound to become a trend-setter in the way genetic diseases are going to be addressed in future.
In fact, according to Jennifer Pardo Habashi, M.D., if this way of finding a cure by investigating the molecular basis of the disease succeeds, then other diseases could be investigated in the same way.
However, does this completely eliminate the need for further monitoring this drug’s performance as far as sufferers of MFS are concerned?
No. A study scheduled to start in the fall of 2006 is aimed at exploring further details in human subjects i.e., on people affected by MFS.
