An Update on Human Gene Therapy - Autumn 1992

It was that Augustinian monk, Gregor Mendel experimenting with his smooth and wrinkled garden peas in the 1860s who led us to an understanding of genetic inheritance.  Then in 1953 it was Francis Crick’s and James Watson’s Nobel prize-wining work on the structure of deoxyribonucleic acid (DNA) that showed it to be the ‘messenger’ of the genetic code.  Then for the last 20 years recombinant DNA technology, or so-called genetic engineering, has been the much hyped technique.  Now there is gene therapy.  Ten years ago this sort of therapy was mere speculation, today it is reality.  What it is?  Is it good, bad or indifferent?  How is it done?  What has it done?  What about its future?

Every cell of your body (except the germ cells, namely, sperm or ova) contains 46 chromosomes and each of these contains your genes packed in coils of DNA.  These genes contain the codes for a myriad of proteins that constitute and regulate our bodies (that’s not a reductionist statement because we are more than just our physical being).  We should marvel at this complexity – every human cell contains over 3 billion codes in its DNA and every human adult carries about 120,000 million miles of DNA strands in his or her body.

It is all mightily complicated, so perhaps it is not surprising that the system sometimes goes wrong.  Indeed, we are all carriers of defective genes, but diseases are not necessarily expressed in us or in our offspring because some, like breast cancer, are the result of the interaction of several faulty genes and we do not carry all of them, or because though you may be a carrier of say, cystic fibrosis, your spouse is not, or because other factors, like diet and environment also play a part in the onset of such diseases.

Recently advances have been made in screening for genetic diseases.  Carriers of cystic fibrosis can now be detected by analysing cells scraped from the inside of the mouth.  A benefit of such screening might be a personalised life plan; if you were predisposed to a heart disease, then you could be advised, ‘do this, don’t do that.’  Predisposition is the buzz-word.  And it is now being applied to diseases like schizophrenia, depression and Alzheimer’s.  But screening can have a downside.  Employers will want us screened, so will insurance companies; who we marry may be a problem; with whom and how (probably by IVF and then embryo selection) we have our children may be controlled to lessen the incidence of genetic diseases.  In the 1970s a sickle cell anaemia screening programme in the US went awfully wrong; there was discrimination and job dismissals of healthy people because the tests were inaccurate.

In a similar way, although we can now state, ‘Yes, you are, or no, you are not a carrier of cystic fibrosis, there is still a 15% uncertainty factor and this is appallingly unnerving for such people.  Or what about the woman who is told there is a 1 in 5 chance that her child will suffer from schizophrenia?  What about her anxieties?  Could she cope?  Screening is only sensible if a proper cure is available.  Can gene therapy help?

What is gene therapy?
Basically, it is inserting a healthy gene into body cells carrying a defective gene.  There are three types of potential gene therapy.  First, germline therapy, that is inserting genes into gametes (ova or sperm) or the gamete-producing cells.  Second, zygote gene therapy performed on a fertilised ovum (a zygote) in conjunction with IVF.  This may be effective for diseases like cystic fibrosis because all affected tissues would be changed.  These two therapies would be heritable, that is, they are a form of eugenics.  Third, somatic gene therapy, that is inserting genes into cells, such as bone marrow cells to cure a disease like thalassemia, which is a sometimes lethal form of anaemia.  This treatment does not cause inheritable changes and is more similar to current medical procedures such as bone marrow transplants.

At the moment only somatic gene therapy is being used and the most promising candidates for treatment are disorders caused by the impairment of a single gene – as opposed to those caused by multiple genes, or even whole chromosomes, like Down’s syndrome.  A disease that fits this criterion is a rather rare condition known as severe combined immunodeficiency (SCID), where because of their limited resistance to infection, patients have to live inside those sterile bubbles.  SCID is cause by a faulty gene that should produce the enzyme, adenosine deaminase (ADA); SCID patients thus have an ADA deficiency.

How is gene therapy done?
The most successful strategy so far used involves viruses and their ability to enter a cell bringing their own DNA with them.  Some viruses can be engineered to contain particular DNA sequences of the correct, healthy gene, but there are huge technical problems concerned with packaging enough of the right sort of DNA, and in addition, most viruses do not readily splice their genetic material into the genes of the cells they infect.

What has been done so far?
The first US-approved clinical trial of a gene therapy started in September 1990 with a four-year-old girl, Ashanti DeSilva, suffering from ADA deficiency.  She had been on enzyme replacement therapy for two years., but the efficacy of this was decreasing as shown by increased infections.  So once a month, some of her blood cells, called T-lymphocytes, which mastermind the workings of the immune system, were sampled, grown in the laboratory, incubated with a viral vector (which carried the normal ADA gene), then these cells were infused back into her.  Over the next 10.5 months she had seven more infusions.  Her clinical condition improved and the treatment periods were lengthened to 3-5 month intervals.  Another girl, aged nine, has begun a similar regime.  Both have shown improvement; they are now attending school regularly and have had no more than an average number of infections, also no significant side effects have been noted.  This approach requires repeated treatment because the effect lasts only as long as the life of the corrected T-cells, so it is not a cure, but it marks a watershed in gene therapy.

Another hereditary disease, hypercholesterolaemia which leads to premature death from heart attacks, has been treated by a similar method since early 1992.  The cause is a faulty gene in the liver that produces a defective version of a protein called low density lipoprotein (LDL) receptor, which controls the cholesterol levels in the body.  The patients have about 15% of their livers removed, these samples are homogenised and the liver cells isolated.  The cells are then exposed to a virus that has been genetically engineered to contain the correct DNA sequence for the LDL receptor.  The treated cells are injected back into the patient’s liver via a vein.  Once there, the idea is that they will implant, grow and produce the required protein.

Such trials are now starting regularly.  In China, a therapy for haemophilia B has just begun; results are not yet available.  During June 1992 two firsts in gene therapy were achieved.  A corrected gene was injected directly into the tumour of a 67-year-old US woman with a malignant melanoma – it was the first time that such a gene had been put directly into a human patient.  Also it was the first time a non-viral vector had been used to deliver the modified gene – in this case the vector was liposomal cells.  The principal investigator at the University of Michigan, Gary Nable said, ‘We have begun to use DNA as a drug.’

Is gene therapy safe?
Such treatments are certainly experimental and medical science is invariably inexact.  Nevertheless, a recent report from a leading scientist in the field summarised 106 monkey-years and 23 patient-years’ work with viral-mediated gene transfers.  No side effects, pathology or malignancy have been reported.  Nevertheless, the danger always exists of producing a germline mutagenic event during gene insertion.

Is gene therapy ethical?
Some fairly profound questions are now being asked.  Do infants have the right to inherit unmanipulated genes?  What about informed consent for patients who do not yet exist?  At what point do we cross the line of ‘playing God’?  What about ‘enhancement’ experiments, inserting genes to improve desired physical or mental characteristics?  When does ‘enhancement’ become ‘treatment’ and vice versa?  But such pertinent questions have a habit of being swept away by the momentum of scientific achievement.

Currently, there is a broad consensus that somatic cell gene therapy for the treatment of a serious disease is an ethical option.  And while there is still considerable opposition to germline therapy, this should not be misconstrued as a permanent moratorium.  As Sir Walter Bodmer, president of the Human Genome Mapping Organisation has said, ‘Most of us believe this (germ cell therapy) is something we shouldn’t do because we don’t know enough about it.’  Even Baroness Warnock tends to agree, but she does not rule out germ cell therapy for all time.  However, W. French Anderson, a leading US molecular scientist, is perhaps more realistic when he states that, ‘The feeling (my italics) of many observers is that germline gene therapy should not be considered until much more is learned …’  It would be naive of us to think that germline therapy will not be started sometime, somewhere, by someone.

What of the future?
As already mentioned, one of the current major problems is controlling the vector, or delivery system, of the corrected gene.  Viruses, which can invade cells and control the genetic mechanisms, are considered the best available at present.  But there are still many questions.  How safe are they?  How specifically can they insert the right information into the right tissue?  How long will they continue to function?  When satisfactory vectors are available, gene therapy may have more impact upon medical science.  Or will it?  Certainly, today’s procedures, whereby cells are removed from a patient, the desired gene inserted and the gene-corrected cells returned, are too specialised, too expensive and too labour intensive.  Gene therapy will have a major impact only when vectors are developed that can safely be injected into patient, like insulin is now.  A wider range of diseases may be treatable in the next few years, but (like IVF) it will be for the thousands rather than the millions of patients.  We should also remember that as radical as gene therapy is, it cannot cure all human diseases.  Most illnesses are not genetic, most are caused by agents such as microorganisms and malnutrition.

Unlike Baroness Warnock, I do believe in the ‘slippery slope’ of medical ethics.  She maintains that we are in safe hands – medical practice will be regulated by society, so nothing terrible will happen.  I maintain something terrible is about to happen – some genetic experimenters are already tiptoeing on the edge and looking longingly down that slope!  And a brief look at the recent history of medical ethics will bring no comfort to the morally sensitive.  The 1967 Abortion Act was designed to help with a few problem pregnancies – now, 25 years later, more than 600 abortions are performed each day in England Wales.  As Schaeffer and Koop warned us years ago, ‘Practices once labelled unthinkable are now considered acceptable.’

So far, we have not begun any gene therapy in the UK, but it will come.  Be warned, be ready and beware!