Gene Therapy for Diseases of the Lung

Kenneth Brigham, Kenneth Brigham

• Editore: CRC Press
• Anno: 2020
• ISBN:
  9781000145922
• Edizione: 1
• Argomento: Medicina
• Categoria: Teoría, práctica y referencia médicas

This up-to-the-minute and comprehensive resource lucidly covers gene therapy for lung diseases from existing technologies delivering foreign DNA to the lungs via the airways or circulation to promising new approaches for the further development of safe and efficient gene delivery systems.

Part One OVERVIEW

1 Human Gene Therapy: The Initial Concepts

W. FRENCH ANDERSON University of Southern California School of Medicine Los Angeles, California

I. Introduction

A number of reviews and histories of gene therapy have been published (1-5). Rather than repeat the well-worn story of 1980 to the present, this review examines the earliest writings that envisioned the concept of gene therapy in human beings. Because some of the sources are a bit difficult to obtain, more extensive quotations than usual will be used to make clear the thinking of the authors. The reader is also referred to the excellent article by Jon Wolff and Joshua Lederberg entitled “An Early History of Gene Transfer and Therapy” (5).

II. The 1960s

The earliest references that specifically address a scientific approach to carry out human gene therapy are in 1966; the original thinkers were Edward Tatum and Joshua Lederberg. However, as early as 1963 Lederberg wrote in an article “Biological Future of Man” (6):

We might anticipate the in vitro culture of germ cells and such manipulations as the interchange of chromosomes and segments. The ultimate application of molecular biology would be the direct control of nucleotide sequences in human chromosomes, coupled with recognition, selection and integration of the desired genes....

On May 26,1966, a symposium took place at Columbia University College of Physicians and Surgeons in New York City entitled “Reflections on Research and the Future of Medicine.” The symposium was published in book form, and the contribution by Tatum was also published separately (see Ref. 7). Tatum addressed human genetic engineering directly:

Finally we can anticipate that viruses will be used effectively for man’s benefit, in theoretical studies concerning somatic cell genetics and possibly in genetic therapy...We even can be somewhat optimistic about the long-range possibility of therapy based on the isolation or design, synthesis, and introduction of new genes into defective cells of particular organs, (p. 33)

I would define genetic engineering as the alteration of existing genes in an individual. This could be accomplished by directed mutation, or by the replacement of existing genes by others.. . . Precedents for the introduction or transfer of genes from one cell to another exist in microbial systems, and now are being tried with mammalian cells in culture....

Hence, it can be suggested that the first successful genetic engineering will be done with the patient’s own cells, for example liver cells, grown in culture. The desired new gene will be introduced, by directed mutation, from normal cells of another donor by transduction, or by direct DNA transfer. The rare cell with the desired change will then be selected, grown into a mass culture, and reimplanted in the patient’s liver, (p. 43)

Severe Ochoa, in a lengthy comment after Tatum’s presentation, ended with the following statement (only reproduced in the book version of the symposium):

I have been impressed by Dr. Tatum’s speculations, shall we say, on genetic engineering. I must confess that I have often been embarrassed by the question: What will be the practical implications of the remarkable developments in molecular biology? Will we be able to fix genes? Will we be able to make genes to order?

There can be no doubt that a wide gap between basic knowledge and possible applications still exists. However, some of the remarks made by Dr. Tatum may not be as farfetched as they might have sounded some time ago—in particular, as regards the possibility of introducing genic material with the required characteristics: either by direct transfer of the DNA or through transduction. Further, one can envisage the possibility of utilizing nonpathogenic viruses for transfer of fragments of the genome, containing the desired traits, from cells in culture to the organism.

In the September-October 1966 issue of The American Naturalist, Lederberg addresses the concept of engineering human cells in an article entitled “Experimental Genetics and Human Evolution” (8):

The cultural revolution has begun its most critical impact on human evolution, having generated technical power which now feeds back to biological nature. The last decade of molecular biology has given us a mechanistic understanding of heredity, and an entry to the same for development. These are just as applicable to human nature as they are to microbial physiology. Some themes of biological engineering are already an inevitable accompaniment of scientific and medical progress over the next five to 20 years.

The sharpest challenges to our pretensions about human nature are already in view—and may be overlooked by too farsighted focussing on more sophisticated possibilities, like “chemical control of genotype”. (To save repeating a phrase, let me call this genetic alchemy, or algeny). (p. 521)

This leads us finally to algeny. Man is indeed on the brink of a major evolutionary perturbation, but this is not algeny, but vegetative propagation. (No one will be surprised that Haldane had anticipated this reasoning years ago.) [Note: see Ref. 9.]

For the sake of argument, suppose we could mimic with human cells what we know in bacteria, the useful transfer of DNA extracted from one cell line to the chromosomes of another cell. Suppose we could even go one step further and sprinkle some specified changes of genotype over that DNA. What use could we make of this technology in the production as opposed to the experimental phase?

Repair genetic-metabolic disease? ...

To recapitulate, if the desired effect is achieved by modifying some somatic cells, the same end is available by transplanting cells already known to have these properties. In general this should be much easier than systematically changing the existing ones....

If we have efficacious methods for testing and selecting new genotypes, do we have much need for algeny? Would not recombination and imitation give ample material for test? Perhaps for some time. But I would credit the possibility of designing a useful protein from first premises, replacing evolution by art. It would then be requisite to implant a specified nucleotide sequence into a chromosome. (pp. 526-527)

Thus, in 1966, the concept of genetic engineering of human beings was clearly delineated. In a January 8,1967, column in The Washington Post (10), Lederberg states:

Dr. Rogers points out how to cure a genetic disease, like phenylketonuria, which causes severe mental retardation. We would find a silent virus that encodes for the missing enzyme, phenylalanine hydroxylase. We would then infect the infant with this virus. Our present knowledge of virus genetics and biochemistry supports even grander expectations—to breed viruses for calculated virogenic effects.

And again in a January 13,1968, column (11) in the same paper:

It is a scheme that we might call “virogenic therapy”. This is an extension of the already well-founded use of tempered live viruses as vaccines to stimulate immunity. ... The infection of a cell by a virus is therefore tantamount to adding some new genes to that cell....

We can, however, think of extracting the DNA molecules that code, say, for insulin and chemically grafting these to the DNA of an existing tempered virus. These new hybrid viruses would then have to be very carefully studied and perhaps modified even further, to select those appropriate for virogenic therapy in man.

The first discussion of the social/ethical implications of human genetic engineering was in the August 11,1967, issue of Science, where Marshall Nirenberg wrote a thoughtful editorial entitled “Will Society Be Prepared?” (12). In it he stated:

My guess is that cells will be programmed with synthetic messages within 25 years. The point which deserves special emphasis is that man may be able to program his own cells with synthetic information long before he will be able to assess adequately the long-term consequences of such alterations.... When man becomes capable of instructing his own cells, he must refrain from doing so until he has sufficient wisdom to use this knowledge for the benefit of mankind.

Two other scientists discussed human gene therapy at this time. In December, 1967, following the announcement of the first in vitro synthesis of DNA, Arthur Komberg said (13):

It may ...