Methods and Compositions for Cellular Reprogramming

Abstract

Compositions and methods useful for the treatment of aberrant programming diseases, particularly those associated with aberrant apoptosis are disclosed

Description

[0001]This application is a divisional application of U.S. patent application Ser. No. 08 / 472,801 filed 7 Jun. 1995, now U.S. Pat. No. 7,517,644, which is a Continuation-in-Part of co-pending application Ser. No. 08 / 426,781, filed 22 Apr. 1995.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention relates to methods and compositions useful in treating disorders in which the direct cause of the clinical disorder is the expression in the primary diseased cells of a differentiation program that does not normally exist. Such disorders are hereinafter referred to as Aberrant Programming (AP) Diseases. The invention also relates to method and compositions useful in therapeutically reprogramming normal cells.[0004]As will be discussed more fully hereinafter, the AP diseases of this invention constitute a new disease classification and there is presented a novel molecular model of pathogenesis for these diseases. According to the molecular model of this invent...

AI Technical Summary

Benefits of technology

The patent describes a method for treating diseases by reprogramming cell behavior through manipulating the expression of certain genes. The method involves using specific molecules called TRs (transcriptional regulators) that control the expression of these genes. The patent also describes a computer-based method for identifying specific sequences in the genes that can be targeted by these TRs. The technical effects of this invention include the ability to treat previously untreatable diseases such as AIDS and cancer by reprogramming cell behavior.

Problems solved by technology

Also, it has been shown that transient inhibition in a leukemia cell line resulted with an ODN against myc; however, unfortunately, a comparable inhibition against normal cells occurred (Zon et al patent).

The fundamental problem with the foregoing part is that it is based on the notion that the expression of specific molecular abnormalities (altered regulation or mutation of endogenous genes or expression of exogenous genes) in the disease cells of these patients directly cause the clinical pathological features of the AP disease.

Balloon angioplasty damages the endothelium underlying the region of treatment and causes intimal migration and proliferation of the SMC over the length of the damaged blood vessel.

Specifically, coronary blood vessels of pigs were damaged by balloon angioplasty.

For example, an antisense ODN capable of blocking SMC proliferation by a reprogramming effect would not be able to block the proliferation of human cells in general.

This possibility remains because the appropriate experiments have not yet been done.

Second, investigators have used computer models of the secondary structure of mRNA to “visualize” mRNA regions that might be susceptible to ODN targeting; these structural modeling procedures are not, however, highly predictive of the actual secondary structure of the mRNA in situ.

A number of difficulties, however, have also been reported in the use of antisense ODNs in in vitro studies, none of which have proven to be insurmountable, however, in view of the existing art and technology.

In general. problems in the in vitro use of antisense ODNs (most commonly phosphorothioates) have centered around what has been viewed as “poor uptake” and / or the production of unintended biologic effects; i.e., non-antisense effects.

Hence, what has been referred to as the “poor uptake” of ODNs by some cell types in vitro may in large part reflect the use of antisense ODNs that are not properly designed and are, therefore, not optimally potent.

Phosphorothioates per se have been found to be relatively non-toxic, although a few particular ODNs have produced unintended toxic effects in animals.

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