Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-11-29
2002-06-25
Clark, Deborah J. R. (Department: 1633)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S455000, C424S269100, C536S023100, C536S023200
Reexamination Certificate
active
06410250
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the field of medical devices, and more particularly, to methods and compositions for sustained delivery of therapeutically-significant substances.
BACKGROUND OF THE INVENTION
A number of diseases are caused by disorders in cellular metabolism. For many of these diseases the nature of the metabolic defect has been identified, and the rapid progress of biomedical research continues to further our understanding of the precise mechanisms involved. For example, Type I diabetes is known to result from defective glucose metabolism associated with decreased levels of insulin, whereas different cancers are due to defective control of cellular division and proliferation associated with mutations in a variety of cellular genes, many of which have been identified. Many disorders in cellular metabolism are caused by somatic or hereditary genetic mutations which result either in inappropriate expression of a given gene product or expression of a defective gene product. However, environmental assaults such as chemical poisoning, physical damage or biological infection can also result in specific defects in cellular metabolism. In addition, cellular aging often results in metabolic disorders. Understanding the nature of a given metabolic disorder identifies targets/goals for an effective treatment.
A traditional approach to treatment consists of administering systemically, to a patient, a pharmaceutical compound or drug that overcomes the metabolic disorder. For example, administering exogenous insulin to a patient alleviates the symptoms of Type I diabetes. There are, however, several drawbacks to this type of drug therapy. For a pharmaceutical compound to be effective, it must be administered so that it reaches its site of action at an appropriate concentration. If the compound is provided systemically, whether administered orally or by injection, undesirable side effects may be caused by the systemic levels of the compound required for it to be effective at its site of action. This is the case for many chemotherapeutic agents used to treat various forms of cancer. Current attempts to overcome this problem consist of trying to target pharmaceutical compounds to their desired site of action for sustained periods of time at effective concentrations. There is not yet a reliable and general method for such targeted drug delivery.
An additional problem with traditional drug administration is that the drug must be stable and transportable to its site of action. For many diseases, the most appropriate therapeutic compound would be a specific protein, especially if the disease results from the absence of a functional form of that protein. However, delivering any given protein to its desired site of action can be complicated by its susceptibility to denaturation and proteolytic degradation, and by poor mobility to its desired site of action.
An alternative approach is gene therapy which attempts to overcome these problems by circumventing the requirement of transporting a protein to its site of action. The goal of gene therapy is to provide DNA encoding the desired protein to the site of action. The DNA then is transcribed and translated to produce the protein in therapeutically effective concentrations at the appropriate site in the body. However, gene therapy also faces a delivery problem of how to get the DNA to the appropriate cells. Current approaches to solving this problem consist of using viral vectors, liposome encapsulation, direct injection, or complexation with carrier proteins. At present, none of these approaches provides an effective and general method for getting DNA to any desired site of action within the body. Current gene therapy technology also does not address the required duration of therapy. Hereditary diseases, for example, might require constant therapy to correct the inherited metabolic disorder. On the other hand, cancer treatment may only be needed for a time sufficient to destroy the cancer cells.
There is, therefore, a need in the art for effective devices and methods for delivering physiologically useful compounds to any desired site of action, in a controlled fashion. It is an object of the present invention to provide such devices and methods.
SUMMARY OF THE INVENTION
A novel approach to the delivery of drugs and other therapeutic substances has now been discovered. The present invention uses genetic mutations to exploit certain innate characteristics of a group of unicellular organisms known as protozoa. By genetically modifying these organisms in accordance with the present invention, the skilled practitioner can now use these organisms as improved devices for the sustained delivery of drugs and other substances.
The rationale for using these organisms as delivery devices includes the following: First, these organisms have evolved a sophisticated ability to infect a host and evade their host's immune defenses. Consequently, these organisms can persist in their host in an undetected and undisturbed state for long periods of time. As taught herein, this characteristic can be exploited to achieve sustained, in vivo delivery of a drug or other therapeutic. Moreover, by practicing the genetic manipulations disclosed herein, an organism's ability to persist in its host can be closely controlled. In fact, an organism can be engineered so that it can be subsequently eliminated on demand. Furthermore, the number of organisms in the host as well as the dose of drug or substance delivered to the host can also be closely controlled using the present invention.
Second, these organisms have evolved very specific, natural tissue preferences. Consequently, these organisms reside and persist in specific tissues in their respective hosts. Moreover, protozoa as a group reside in virtually every tissue or organ of vertebrates and invertebrates. As taught herein, this characteristic can be exploited to achieve targeted, tissue-specific delivery of a drug or other therapeutic substance. Currently, the only available type of targeted, sustained in vivo delivery relies on gene therapy, however, gene therapy cannot be similarly controlled, is often viral-vector mediated, and can result in undesirable and/or permanent alteration of the recipient's genome. Thus, the teachings of the present invention overcome the limitations of gene therapy, as well as overcome numerous problems associated with more conventional drug therapy methods, such as unnecessary systemic exposure, toxicity, poor transportability, degradation and stability to name but a few.
Accordingly, the teachings of the present invention provide a device for delivery of a drug or therapeutic substance which is sustained, targeted, reversible and virus-free, without necessarily exposing the recipient to permanent genetic alterations. In one aspect, the present invention features a sustained delivery device comprising an isolated, conditionally defective unicellular organism expressing a therapeutically-significant substance. The genome of this organism is genetically altered to lack a naturally-occurring nucleotide sequence defining a genetic locus responsible for a selectable phenotype, and encode an expression product for sustained delivery. In some embodiments, the unicellular organism is a diploid organism. In other embodiments, the organism is an asexual diploid organism. In certain currently preferred embodiments, the organism is a protozoa, more preferably a parasitic protozoa. The expression product of the present device can be encoded by a heterologous gene. Currently preferred are genes encoding a hormone, enzyme or neurotransmitter, however, any substance of therapeutic significance is contemplated. In other embodiments disclosed herein, the device can comprise an exogenous marker gene. For purposes explained herein, a currently preferred selectable phenotype is one associated with a conditional defect in metabolic function such as, but not limited to, conditional auxotrophy.
In yet another currently preferred embodiment, the above-mentioned con
Beverley Stephen M.
Gueiros-Filho Frederico J.
Vaccaro Dennis E.
Clark Deborah J. R.
Sorbello Eleanor
Symbiontics, Inc.
Testa Hurwitz & Thibeault LLP
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