Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-04-23
2002-06-04
Martin, Jill D. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S093210, C435S455000, C435S456000, C435S069100, C435S320100, C435S325000
Reexamination Certificate
active
06399585
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to lung cells having a novel phenotype, morphology, and immunoprotectant properties. The invention further relates to cell lines derived from such cells and methods for producing such cells, both in vivo and in vitro. The invention additionally relates to expression products of such cells and cell lines.
2. Background of the Technology
Genetic information in living creatures is contained in deoxyribonucleic acid (DNA) which is the chemical that makes up genes. Formed from long chains of “nucleotide bases”, genes are the building blocks of life. The nucleotide bases, guanine (G), cytosine (C), adenine (A), and thymidine (T), bond together into long chains that provide the recipe for what our bodies make. Genes dictate the production of chemicals (proteins) that make our bodies function and create our appearance, such as our sex and our hair, eye, and skin colors. Genes, however, can also be missing, defective, or not fully operational which can lead to serious medical problems. Certain medical problems that are genetic in origin are cystic fibrosis (a severe disease that commonly manifests itself in chronic lung problems), adenosine deaminase deficiency (“ADA deficiency”, which results in a nearly nonfunctioning immune system in a patient), &agr;1-antitrypsin deficiency (“AAT deficiency”, which results in liver dysfunction and emphysema style malfunction in the lungs), among others.
The recipe, mentioned above, stems from the fact that genes “code” for, and “express”, proteins within cells. That is, the cellular machinery within a cell reads the genetic code that is present within the cell and manufactures (expresses) the appropriate protein. The resulting proteins are used in a variety of different processes in the body. Such proteins can be used in “signaling” the cells to do something, used by cells to accomplish a task, or the like. Where a gene is missing or defective, the cells are incapable of properly functioning in signaling, accomplishing their task, or the like. Where a gene is underexpressed, i.e., makes too little protein, there may be insufficient quantities of the protein present in the body to provide proper function or the like. In other cases a gene may be “overexpressed”, i.e., too much protein is made, which may lead to undesirable consequences. It is this latter case that is believed to play a role in certain cancers, for example, oncogenes are genes that become overexpressed and appear to play a role in the development of certain cancers.
Gene therapy is a therapeutic approach in which a disease or genetic defect in a patient is treated or corrected through providing a “foreign” gene that is either missing, defective, underexpressed, or will help treat the disease. The potentials of gene therapy are, therefore, enormous. In theory, many diseases can be treated or cured through the use of gene therapy.
There are many gene therapeutic approaches that are currently being studied, either preclinically, in animals, or clinically, in human patients. One of the earliest gene therapeutic approaches that was tried (in mid-1991) was the correction of ADA deficiency. ADA deficiency is an enzymatic deficiency. In ADA deficiency, patients are susceptible to virtually any infection or disease—a cold, for example, can potentially be fatal. Suffers from ADA deficiency are forced to live their usually very short lives in an isolation chamber (i.e., a bubble baby).
In the gene therapeutic approach for treating ADA deficiency, in a process known as “ex-vivo” gene therapy, particular immune cells from patients were taken from their bodies and a foreign ADA gene was inserted into the genetic material of the cells using a “retrovirus” (a virus that inserts itself into the DNA of a cell). Such “transduced” or “transgenic” cells were then capable of producing the protein adenosine deaminase. The transduced cells were reintroduced into the patients. It was recently reported that one of the patients, so treated, appears to be producing about 25% of the normal levels of ADA, while another of the patients appears to be producing only about 1% of the normal levels. Generally, in enzymatic type deficiencies, such as ADA deficiency, if one can restore approximately 10% of normal production of protein, the patient should experience generally normal function. Thus, it appears that success was achieved in one of the two patients. See
New York Times;
p. 422, (Oct. 20, 1995), the disclosure of which is hereby incorporated by reference.
Cystic fibrosis (CF) is a genetic disease that afflicts infants in approximately 1 of every 2000 or 9000 births, depending on race. In CF, patients experience severe “endocrine” misfunction. The endocrine system includes all of the cells and organs involved in the secretion of substances, particularly of hormones, in the body. One of the significant symptoms of CF, and a leading cause of death therefrom, is chronic lung problems, including, a thick mucous that fills the lungs, infections, and persistent coughing. In addition, the lungs of the patient with CF are susceptible to repeated bacterial infections which ultimately lead to lung damage and respiratory failure.
A gene, the CFTR gene, has been used in human clinical trials in an effort to restore lung function in patients suffering from CF. Some success has been achieved, however, as in many therapeutic procedures, where a foreign protein or gene is administered to a patient, the body often recognizes such materials as foreign and mounts an attack on the foreign materials, called an immune response.
An immune response is visible in situations where a cut becomes infected with bacteria, the cut swells, becomes red and inflamed, becomes warm, may have pus or the like. In this process, the body has recognized the presence of foreign bacteria and has mounted an attack on it. Further, the body has a system for remembering the foreign bacteria (“memory cells”) so that, in the future, if exposed to the bacteria again, it can mount its attack more quickly.
The immune system, and the response that the immune system mounts, is very useful in protecting our bodies against infection and many diseases. However, the very system that assists us in staying healthy, is often an obstacle to the delivery of genes to a patient. When genes are attacked by the body's immune system, the function of the gene (the gene's ability to produce the desired protein) is often destroyed.
It has been proposed that prenatal fetuses (in utero, prior to birth) may not possess as significant an immune response to foreign genes. It is thought that mammals, at such a stage of development are “immunotolerant.” Immunotolerant essentially means that the immune systems of such animals will not so readily attack foreign genes. This belief is founded on the principal that prenatal fetuses are exposed to multiple foreign genes from the “mother” in addition to the fact that the immune system in the infant is still developing.
In addition to their potential immunotolerance, prenatal fetuses offer yet another advantage over more mature mammals. This advantage is that, in theory, certain genetic defects that compromise the health of the infant upon birth can be treated prior to delivery. CF is an example; chronic lung infections can result in irreversible lung damage. Through providing the CF gene to an infant prior to their delivery from the uterus, the lung problems could potentially be avoided.
Thus, was suggested that prenatal infant mammals would be a good target for gene therapy. Indeed, based on this postulate, several groups have tried to deliver foreign genes to prenatal animals. Such groups injected foreign genes into the amniotic fluid surrounding a prenatal infant mammal. It was expected that the gene would be breathed in and swallowed by the infant as it begins “practicing” using such muscles. The groups initially observed positive results; the injected gene was expressed in certain tissues in the infant mammal. In contrast to the predictions rela
Cohen J. Craig
Larson Janet E.
Sekhon Harmanjatinder S.
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