How Can Gene Therapy Even Be Used On Physically Mature Adults?

I remember the blogger Sam Snyder stating in one of my earliest posts that one way to possibly increase height in the future is from using gene therapy. That has really stuck out in my head and I have been wondering for the longest time exactly how gene therapy can be used to increase in height.

From the Wikipedia article on gene therapy (source HERE)…

Gene therapy is the use of DNA as a pharmaceutical agent to treat disease. It derives its name from the idea that DNA can be used to supplement or alter genes within an individual’s cells as a therapy to treat disease. The most common form of gene therapy involves using DNA that encodes a functional, therapeutic gene in order to replace a mutated gene. Other forms involve directly correcting a mutation, or using DNA that encodes a therapeutic protein drug (rather than a natural human gene) to provide treatment. In gene therapy, DNA that encodes a therapeutic protein is packaged within a “vector”, which is used to get the DNA inside cells within the body. Once inside, the DNA becomes expressed by the cell machinery, resulting in the production of therapeutic protein, which in turn treats the patient’s disease.

Although early clinical failures led many to dismiss gene therapy as over-hyped, clinical successes in 2006-2011 have bolstered new optimism in the promise of gene therapy. These include successful treatment of patients with the retinal disease Leber’s congenital amaurosis, X-linked SCID, ADA-SCID, adrenoleukodystrophy, chronic myelogenous leukemia (CLL), and Parkinson’s disease. These recent clinical successes have led to a renewed interest in gene therapy, with several articles in scientific and popular publications calling for continued investment in the field.

Approach

Scientists have taken the logical step of trying to introduce genes directly into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy andsickle cell anemia. However, this has proven more difficult than modifying bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering them to the correct site on the gene. Today, most gene therapy studies are aimed at cancer and hereditary diseases linked to a genetic defect. Antisense therapy is not strictly a form of gene therapy, but is a related, genetically-mediated therapy.

The most common form of genetic engineering involves the insertion of a functional gene at an unspecified location in the host genome.This is accomplished by isolating and copying the gene of interest, generating a construct containing all the genetic elements for correct expression, and then inserting this construct into a random location in the host organism. Other forms of genetic engineering include gene targeting and knocking out specific genes via engineered nucleases such as zinc finger nucleases, engineered I-CreI homing endonucleases, or nucleases generated from TAL effectors. An example of gene-knockout mediated gene therapy is the knockout of the human CCR5 gene in T-cells in order to control HIV infection.[16] This approach is currently being used in several human clinical trials.[17]

Types of gene therapy

Gene therapy may be classified into the two following types:

Somatic gene therapy

In somatic gene therapy, the therapeutic genes are transferred into the somatic cells, or body, of a patient. Any modifications and effects will be restricted to the individual patient only, and will not be inherited by the patient’s offspring or later generations. Somatic gene therapy represents the mainstream line of current basic and clinical research, where the therapeutic DNA transgene (either integrated in the genome or as an external episome or plasmid) is used to treat a disease in an individual.

Germ line gene therapy

In germ line gene therapy, Germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are integrated into their genomes. This would allow the therapy to be heritable and passed on to later generations. Although this should, in theory, be highly effective in counteracting genetic disorders and hereditary diseases, many jurisdictions prohibit this for application in human beings, at least for the present, for a variety of technical and ethical reasons.

Vectors in gene therapy

Main article: Vectors in Gene Therapy

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by a number of methods. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

Viruses

Main article: Viral vector

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Therefore this has been recognized as a plausible strategy for gene therapy, by removing the viral DNA and using the virus as a vehicle to deliver the therapeutic DNA.

A number of viruses have been used for human gene therapy, including retrovirus, adenovirus, lentivirus, herpes simplex virus, vaccinia, pox virus, and adeno-associated virus.

Non-viral methods

Non-viral methods can present certain advantages over viral methods, such as large scale production and low host immunogenicity. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques that approach the transfection efficiencies of viruses.

There are several methods for non-viral gene therapy, including the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, and the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

Problems

For the safety of gene therapy, the Weismann barrier is fundamental in the current thinking. Soma-to-germline feedback should therefore be impossible. However, there are indications[50] that the Weismann barrier can be breached. One way it might possibly be breached is if the treatment were somehow misapplied and spread to the testes and therefore would infect the germline against the intentions of the therapy.

Some of the problems of gene therapy include:

  • Short-lived nature of gene therapy – Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy.
  • Immune response – Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system’s enhanced response to invaders that it has seen before makes it difficult for gene therapy to be repeated in patients.
  • Problems with viral vectors – Viruses, the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient: toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease.
  • Multigene disorders – Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such asheart disease, high blood pressure, Alzheimer’s disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy.
  • Chance of inducing a tumor (insertional mutagenesis) – If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[51] One possible solution for this is to add a functional tumor suppressor gene onto the DNA to be integrated; however, this poses its own problems, since the longer the DNA is, the harder it is to integrate it efficiently into cell genomes.

Three patients’ deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger in 1999, which represented a major setback in the field. One X-SCID patient died of leukemia following gene therapy treatment in 2003. In 2007, a rheumatoid arthritis patient died from an infection in a gene therapy trial; a subsequent investigation concluded that the death was not related to her gene therapy treatment.

Preventive gene therapy

Preventive gene therapy is the repair of a gene with a mutation associated with a progressive disease, prior to the expression of a medical condition, in order to prevent that expression. There are a number of considerations:[54]

  • It is hard to get U.S. FDA approval to treat a pre-symptomatic condition because it is hard to predict the complications that may arise, so it is hard to give a risk/benefit analysis. This is an obstacle to long-term therapies.
  • It is easier to gain approval for short-term therapies to treat expressed conditions rather than prevent them.
  • It is not known whether the repair of a mutation will help to treat a condition which has already progressed beyond the initial consequences of that mutation.

Similar to organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the ‘normal’ gene has been difficult because the immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini’s group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy.

In November 2006 Preston Nix from the University of Pennsylvania School of Medicine reported on VRX496, a gene-based immunotherapy for the treatment of human immunodeficiency virus (HIV) that uses alentiviral vector for delivery of an antisense gene against the HIV envelope. In the Phase I trial enrolling five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens, a single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was safe and well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. In addition, all five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in U.S.Food and Drug Administration-approved human clinical trials for any disease.

Me: The problem with height is that is a characteristic that is the result of a multiple of genes all working together to form one overall phenotypical characteristic. We can not target just one gene through viral inoculation and hope that it would be enough to change height. So far, there have been only a few genes that seem to be linked to height but each one only has a very small effect on the overall height. 

If we tried other methods like DNA methylation to silence certain genes, we would have to methylate at least 10 sequencing genes which can lead to results which we may not want in other ways of phenotypical expression. When I think of gene therapy, my vision is the possibility of future parents finding out that their unborn child has a certain hereditary disability which the doctors can go into the zygote and snip and replace a gene.

At this point, I can’t figure out how gene therapy can be used to increase height in physically mature adults.  

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