Mar 19, 2000
Interferon and Down Syndrome
Summary by Dr. Len Leshin, MD, FAAP
|Interferon is a protein in the class of proteins called "cytokines." It's
produced in various types of cells, and it's action in the body depends on which type of cell is making it. There are three types: alpha, beta and gamma-interferons.
To have an effect on a cell, the interferon molecule (like other proteins) must fit into a "receptor" on the surface of the cell, like a key fitting into a lock. With interferon, one receptor handles the alpha and beta versions, while a second receptor handles the gamma-interferon.
|Back in the late 1970s, it was found that the 21st chromosome carried the gene for producing the alpha-beta receptors. This fit quite nicely with the observation a few years previously that fibroblasts (a cell of the connective tissue, which forms collagen) from people with DS had an increased sensitivity to the antiviral activity of fibroblast interferon. This makes sense if you think about a lot of keys trying to fit into a few locks; the more locks there are, the more keys you can use, and the bigger effect noted. The effects were also noted to include sensitivity to interferon's cell growth inhibition. One specific researcher, Dr. Leonard Maroun of Illinois, noted this fact and has been working on this topic for the last 20 years:|
Interferon effect on ribosomal ribonucleic acid related to chromosome 21 ploidy.
Yes, that's a mouthful. The bottom line here is that the fibroblasts from subjects with DS were very sensitive to the effect of interferon: namely, a decrease in cellular protein synthesis.
Interferon and Down Syndrome: 1980 to 1994
In 1980, Dr. Maroun subsequently theorized the following:
1. Interferon could be involved in the physical features and development of the child with DS. Since viral infections cause the body to produce interferon, exposure to interferon in the womb may cause an increased effect via growth inhibition of cells on the fetus. The more infections the mother had, the more interferon the fetus would be exposed to and the more "affected" the baby would be. A pregnancy free of viral infections might produce a baby with few of the features commonly associated with DS.
2. A study in 1965 seemed to show that an increase in the incidence of infectious hepatitis (hep A) was followed nine months later by an increase in the number of births of babies with DS, even if the mother of the baby showed no signs of infection with hepatitis. (This was before serum markers could prove exposure or non-exposure to hep A.) If a woman over 35 years of age had an oocyte sensitive to interferon,and there was an antiviral response in her body at the time of meiosis, the interferon could produce non-disjunction in the oocyte, leading to trisomy 21.
A medline search for this topic in the 1980s shows only a handful of studies. If you eliminate the studies just focusing on immunology and not interferon specifically, the remainder are involved with either mapping the receptor gene to the specific spot on the 21st chromosome, and confirming in different ways the increased sensitivity of DS cells to interferon. For example:
Synthesis of interferon-induced polypeptides in normal and chromosome 21-aneuploid human fibroblasts: relationship to relative sensitivities in antiviral assays.
However, two other interesting studies show up:
Expression of the 210 kDa neurofilament subunit in cultured central nervous system from normal and trisomy 16 mice: regulation by interferon.
Commentary: Down's syndrome, interferon sensitivity and the development of leukaemia.
Interferon and Down Syndrome: 1995 to 2000
OK, here's where we catch up with Dr. Maroun again:
Interferon action and chromosome 21 trisomy (Down syndrome): 15 years later.
So...could blocking interferon have any measurable effects in DS? Here are three studies that suggest it might:
Anti-interferon immunoglobulins can improve the trisomy 16 mouse phenotype.
Interferon and trisomy 16 mouse fetal heart development and function.
What else interesting is there? Well, Dr. Maroun makes an interesting point on his website that many side effects of interferon therapy (given for cancer) are also features seen in Down syndrome (DS):
Interferon side effects: neurotoxicity, memory loss, frontal lobe encephalopathy
DS: learning difficulties, small frontal lobes
Interferon side effects: cardiotoxicity
DS: heart defects
Interferon side effects: hypothyroidism
Interferon side effects: autoimmune disease
DS: autoimmune disease
Interferon side effects: deafness
DS: hearing loss (mostly conductive but some neuronal)
Interferon side effects: growth inhibition
DS: short stature
Anti-interferon, Meiogen and Controversy
Dr. Maroun has set up a company called Meiogen Biotech in order to develop an anti-interferon ("Antiferon") drug for testing purposes. He states that testing humans is still 2 to 3 years and several hundred thousand dollars away, but he is attempting to get funding at the present time.
The first step on that road has been accomplished, as the US Patent Office has given Dr. Maroun a patent for the intellectual property rights for "Methods of Treatment of Down Syndrome Using Interferon Antagonists." According to Dr. Maroun, this "is an essential first step in the competition for funds in the financial markets."
This research does have its detractors. Critics have pointed out that the entire research to date has been based on animal models that may not be very good models for humans with trisomy 21. Also, the bulk of the research has been done by one investigator with no confirmatory studies to date.
My personal impression is that this is extremely experimental, and needs much more investigational work, but it seems like an interesting direction.
For more information on this company and research, visit Meiogen Biotechnology Corporation.
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