HDAC drugs for autoimmune diseases

Initially it may come as a surprise, but it turns out that some powerful cancer drugs also are useful against autoimmune diseases as well. A good example is the monoclonal antibody rituximab.

In this case the reason is that as a monoclonal antibody, rituximab binds to the protein CD20, which is widely expressed on B cell lymphocytes of the immune system. Once it has bound to the CD20 of a B cell, it may lead to cell death by apoptosis, which is helpful in the case of of B cell cancers such as non-Hodgkin lymphoma and B cell leukemia.

The general pattern here is that some kinds of cancer and some autoimmune diseases both involve the overactivity and proliferation of certain types of immune system cells. A drug that counteracts such pathology may be useful for treating both the associated cancers and autoimmune diseases.

T cells are another large and important class of immune system cells, which we've discussed before (see here). T cells can also be involved in cancer, such as another form of non-Hodgkin lymphoma called cutaneous T cell lymphoma.

There is an FDA-approved drug for this cancer, called vorinostat, also known as suberoylanilide hydroxamic acid (SAHA). We have also mentioned this before, because the compound is a histone deacetylase (HDAC) enzyme inhibitor. HDAC enzymes have the effect of turning off genes, so an inhibitor of a particular HDAC enzyme has the effect of allowing the genes to remain turned on. Some cancers develop because they cause the overexpression of a HDAC enzyme that then turns off genes which would otherwise suppress the cancer. So an inhibitor of the approriate HDAC enzyme boosts the expression of the affected cancer-fighting genes. This is how vorinostat works.

Certain types of T cells can also cause various autoimmune diseases if they get out of control. Normally these T cells should be kept under control by messaging molecules (such as Foxp3) produced by a special type of T cell called a regulatory T cell (T_reg cells). So when a condition develops where there is excessive and harmful activity of T cells, it it may be possible to counteract this by boosting the number or activity of T_reg cells.

And this is precisely what SAHA is apparently able to do – by inhibiting a HDAC enzyme, it raises T_reg cell activity to control the overactivity of other types of T cells, as found in inflammatory bowel disease and various kinds of transplant rejections.

New cancer drugs could help in autoimmune disease

A new class of drugs used to treat cancer might be effective at suppressing overactive immune systems in patients with autoimmune diseases like Crohn's disease, U.S. researchers said on Sunday.

"What we would be proposing would be a therapy that would enhance the body's own immune system's ability to regulate itself," said Wayne Hancock of Children's Hospital of Philadelphia, whose study appears in the journal Nature Medicine.

Hancock said drugs known as histone deacetylases inhibitors, or HDACs, which affect compounds involved in the growth and death of cancer cells, bolstered the production of cells that regulate the immune system in mice.

In one study, the drug helped reverse and prevent inflammatory bowel disease. It also prevented the rejection of heart transplants in other mice. And it stopped rejection of pancreatic cell transplants in other mice.

It's possible that SAHA (i. e. vorinostat, which is distributed commercially by Merck under the name Zolinza) could also work to treat other autoimmune diseases like rheumatoid arthritis. And who knows what other cancer drugs might also have such dual uses?

More: Cancer drugs could fight autoimmune disease

Tags: cancer, autoimmune disease, histone deacetylase enzyme

Disease genes

This is old news (over a month), and it was widely reported in the general media, so I'm sure most readers are aware of it. But it seems important enough to note here, just for the record. It might be considered one of the most important science stories of the year.

Largest Ever Study Of Genetics Of Common Diseases Published

The Wellcome Trust Case Control Consortium, the largest ever study of the genetics behind common diseases such as diabetes, rheumatoid arthritis and coronary heart disease, published its results in the journals Nature and Nature Genetics.

The £9 million study is one of the UK's largest and most successful academic collaborations to date. It has examined DNA samples from 17,000 people across the UK, bringing together 50 leading research groups and 200 scientists in the field of human genetics from dozens of UK institutions. Over two years, they have analysed almost 10 billion pieces of genetic information.

Information about a couple of autoimmune diseases figured prominently in the results.

Amongst the most significant new findings are four chromosome regions containing genes that can predispose to type 1 diabetes and three new genes for Crohn's disease (a type of inflammatory bowel disease). For the first time, the researchers have found a gene linking these two autoimmune diseases, known as PTPN2.

The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease. Autophagy, or "self eating", is responsible for clearing unwanted material, such as bacteria, from within cells. The may be key to the interaction of gut bacteria in health and in inflammatory bowel disease and could have clinical significance in the future.

"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."

There were also findings about genetic factors in obesity, type 2 diabetes, and heart disease. In fact, seven major disease in all:

These are bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis and type 1 and type 2 diabetes.

Interestingly, rheumatoid arthritis is also an autoimmune disease. And the immune system (especially in regard to inflammation) probably plays some role in other ailments on this list.

Most readers here probably understand that very seldom is a single gene ever the sole "cause" of a particular disease. Instead, what has been found, in this study and in others, is a number of variants (called alleles) of a variety of genes, where one of more of the variants, if present in an individual, increases the person's risk of eventually developing the disease – conditioned on the presence of other genetic variations, environmental conditions, and so forth. As another account explains:

Sick Genes

[G]enes, although potent predictors, are not always the sole cause of particular diseases. For instance, environmental factors, lifestyle (diet, exercise, etcetera) and exposure to infections can all play roles in determining whether an individual will develop heart disease, for example. "It's about hundreds of genes in your genome contributing a threshold of genetic susceptibility," Todd says. "It's not about one gene."

Nevertheless, on average, having one copy of some of the newly identified genes raises a person's chances of developing one of the seven studied diseases by 20 to 40 percent, and those with two copies face nearly double that risk, researchers say. "What hasn't been clear is exactly which bits of the genome have an effect and which variants make people more [or less] likely to get a disease," Donnelly notes.

Additional news reports: here, here, here, here.

Tags: genetics, disease genes