2011 ASH Annual Meeting, December 10-13, San Diego, USA

Causes and drug development in ataxia telangiectasia

Dr Richard Gatti – David Geffen School of Medicine UCLA, USA


AT, as we call it as it’s much easier to pronounce, is a rare disorder of children. They’re born looking normal and by one or two years of age they start to stagger and then by ten they’re in a wheelchair for the rest of their lives. And, to make things worse, one out of three of them usually develops malignancy at some time, not necessarily incurable, some can be treated successfully but some cannot.

Is there a high predisposition to cancer?

They have a very strong cancer predisposition, yes.

Why do they have this disposition?

In a word, because they’re missing the ATM protein, AT mutated, that’s where the word comes from, and without this protein they cannot activate the systems that are necessary to repair a double strand break in DNA so it’s a very serious break because a cell cannot survive a replication by having both strands broken. So there’s a special mechanism for repairing that and it involves many proteins, probably over fifty, maybe a hundred.

What are the consequences of this?

It’s broken ends and apoptosis from… just cell death from apoptosis.

Will cells survive and become tumour cells?

No, that’s probably a mechanism that is amplified from any type of a break to the DNA that occurs, that instead of being stitched back up quickly actually begins to expand as a lesion and when it begins to take out large pieces of DNA through translocations and inversions, then you get into these problems with cancer. That area is not well known, there is still a lot of work going on in that area but it’s not really clear exactly how these cells end up as cancers so often.

What is your lab currently working on?

We’re working on the development of a group of drugs that treat the cells that have nonsense mutations by tricking the RNA into read-through. They read through a stop sign; there are typical stop signs, premature termination codons, there are stop signs at the end of a gene too but those don’t seem to be affected by these drugs, probably because they’re in the right context, you know - a period at the end of a paragraph, you don’t question it, but a period in the middle of a word in the middle of the paragraph you probably would ignore it because it doesn’t make any sense. And that’s what a premature termination codon would be, but the DNA machinery and the translation machinery is like a computer – if it’s there, there’s a reaction to it and usually it truncates the translation and it stops the production of the protein and then that protein is foreshortened and it’s basically inappropriate protein and it’s degraded almost immediately because defective proteins can be dangerous to the body too. So it’s taken out quickly and then they end up with no ATM protein. When we test them diagnostically they have little or no ATM protein and these drugs would induce that protein to be made again.

Can these drugs be used against any other diseases?

Research has muscular dystrophy, Hurler’s disease, many of the genetic diseases and, again, not everyone with that disease but those that have those kinds of mutations, but the application is broad, it may be useful even in breast cancer individuals, not the cancer but the genetic defect that leads to the breast cancer susceptibility in those individuals. We’re at what’s called proof of concept and we’re trying to show where this works, does it work all the time, what kind of cells does it not work and then we have a group of drugs and we’re testing to see which one would be the most user-friendly as a medication.

Can you summarise the data you presented at this meeting?

I know that there are a lot of young members of ASH that are here and what I was trying to present to them was that the ataxia telangiectasia phenotype, what the disease looks like, actually we’re beginning to realise is a phenotype, it’s a pattern for recognising other diseases that are missing DNA repair proteins. It makes sense in a way, if the problem is repairing double strand breaks in DNA and you need fifty different proteins, missing one or missing the other is going to end up at the same place, right? And they generally do and what they have in common and what I wanted to alert the younger generation, well everyone, that this is new information since they’re the ones that are just learning medicine. They should think that the AT syndrome is not just for AT, they should begin to look at a lymphoma as a potentially genetic disease, that it may be a manifestation of an AT-like syndrome, a leukaemia, the same thing. Maybe other types of malignancy as well but nothing is as clear as the relationship of lymphomas and leukaemias to the DNA repair disorders that we’re seeing like Nijmegen Breakage Syndrome, they all have peculiar names and they’re very rare but the syndrome seems to be shared by many of these diseases. Another is microcephaly, if you see a child with microcephaly you should be thinking that perhaps it’s genetic and it’s a DNA repair disorder, not because we understand why but we are beginning to observe that most of those diseases have small heads. There are many causes of microcephaly and mental retardation but these are all part of a larger syndrome and that’s what I was trying to address.

The general public thinks treatment, the physician, of course, first thinks diagnosis. You want to put the right label on what a particular child has, that’s the first step towards the right treatment and what I was trying to show is that they should be thinking about these diseases so that they order the right tests to try to focus in on whether or not that individual, for example, with microcephaly or with lymphoma might actually be susceptible or sensitive, hypersensitive, to radiation. So that if you send them for treatment of their lymphoma and no-one was aware that they might be radiosensitive, that the radiotherapy might do more harm than the actual cancer that they’re trying to treat.