Methods for the identification of patients at risk for heart...

Details Methods for the identification of patients at risk for heart... Methods for the identification of patients at risk for heart...

1999-11-24

2001-02-13

Zitomer, Stephanie (Department: 1655)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S091200, C536S023100

Reexamination Certificate

active

06187542

ABSTRACT:

BACKGROUND OF THE INVENTION
Congestive heart failure is a complex clinical syndrome characterized by diminished cardiac contractile function and decreased exercise tolerance. Despite advances in medical therapy, 40% of patients die within one year of diagnosis and 70% are dead at five years.
A number of clinical predictors of survival in heart failure have been identified including age, decreased cardiac output and high blood pressure. However, clinical parameters alone have been of limited value in predicting survival in patients with congestive heart failure. It also appears that the genetic background of the individual plays a role. Accordingly, there is a need to identify genetic markers which are associated with improved or decreased survival in patients with heart failure.
The adenosine monophosphate deaminase 1 (AMPD1) gene is the predominant member of the AMPD multi-gene family expressed in adult cardiac myocytes and adult skeletal muscle. Approximately 20% of Caucasians and African Americans are heterozygous for a single mutant allele, AMPD1(+/−), which specifies a nonsense mutation in the second coding exon of this gene. This mutation leads to premature peptide chain termination and production of truncated peptide which is catalytically inactive. Deficiency in this enzymatic activity in myocytes resulting from the AMPD1 (+/−) genotype may have one of several metabolic consequences. A marked decrease in AMPD1 activity in myocytes may lower the adenylate energy charge in the myocyte by limiting deamination of AMP. A partial reduction in the activity of this enzyme may cause the myocyte to produce more adenosine following ATP catabolism. Increased adenosine production may be beneficial as adenosine is known to have potent cardioprotective effects. In patients with congestive heart failure, the residual cardiac myocytes experience greater metabolic demands; therefore, a reduction in AMPD activity may lead to increased adenosine production which could improve cardiac function.
Accordingly, compositions and methods which inhibit AMPD activity are desired. Further, methods of identifying patients who are likely to develop congestive heart failure and identifying those who may benefit from a cardiac transplant are also desired.
SUMMARY OF THE INVENTION
AMP deaminase activity has now been found to influence the clinical outcome in patients with heart failure. Patients with a mutant allele of the AMP deaminase 1 gene (AMPD1) have been found to have a significant prolongation of life if they develop congestive heart failure compared to patients without the mutant allele. Further, it has been found that patients who inherit at least one copy of this mutant allele, compared to patients who are homozygous for the wild-type allele, exhibit a longer duration of heart failure symptoms before requiring referral for cardiac transplant. Accordingly, it appears that one or more of the metabolic consequences of reduced AMPD activity provides for improved prognostic and survival advantages for individuals who inherit this AMPD1 mutant allele and subsequently develop heart failure. It is thus believed that reduction of AMPD activity in individuals suffering from congestive heart failure who are homozygous for the wild-type allele will improve the prognostic and survival advantages in these individuals.
Accordingly, an object of the present invention is to provide compositions and methods for inhibiting the AMPD1 enzyme and related enzymes from the AMPD1 gene family for the treatment of patients with congestive heart failure.
Another object of the present invention is to provide methods of predicting clinical outcome of patients suffering from congestive heart failure and identifying those patient most likely to benefit from a cardiac transplant which comprises identifying patients with a mutant allele of the AMPD1 gene.


REFERENCES:
patent: 4912092 (1990-03-01), Gruber
Morisaki et al. “Molecular basis of AMP deaminase defiency in skeletal muscle” Proc. Natl.Acad. Sci. USA 89:6457-6461.
Loh et al., “Cardiac Transplantation in the 1990s”,Card. Rev.1, 218-227 1993.
Morisaki et al., “Molecular basis of AMP deaminase deficiency in skeletal muscle”,Proc. Natl Acad. Sci. USA1992 89, 6457-6461.

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