Proteintech

ALS Research: From SOD1 to Chromosome 9

November 9, 2011 at 9:31 am | Posted in News, Scientist interviews | 4 Comments
Tags: ALS, amyotrophic lateral sclerosis, antisense technology, C9ORF72, Chromosome 9, Don Cleveland, frontotemporal lobar dementias, FTD, ISIS Pharmaceuticals, Lucie Bruijn, The ALS Association, TREAT ALS

The ALS Association are co-sponsoring a satellite meeting this month at The Society for Neuroscience’s (SFN) Annual Meeting. In the run up to Proteintech’s visit to The SFN 2011 I met with Dr. Lucie Bruijn, Chief Scientist of The ALS Association, to talk SOD1, ask where ALS research stands at present and learn about a very recent and exciting find in this field…

Around 20 years ago the cause of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) was still completely unknown, leaving little hope in terms of developing diagnostics and treatments for this devastating, motor neuron-destroying condition. Then, with the discovery of a link to an SOD1 mutation on chromosome 21q in the early 1990s, everything changed for ALS research. With this first piece of the ALS puzzle in place, there was a glimmer of hope on the horizon in the form of SOD1. The newest discovery in ALS research – a link between ALS and a region of chromosome 9 – is tipped to be a breakthrough of the same (if not larger) magnitude as the SOD1 finding; essentially, the direction taken with the chromosome 9 discovery could parallel the story with SOD1. And who better to talk us through that story than Lucie Bruijn?

The SOD1 story

Now Chief Scientist of The ALS Association, Bruijn has been involved in ALS research ever since the SOD1 breakthrough and is about to embark on coordinating the next step in chromosome 9 research.  Her background in ALS began when she took up postdoctoral work with Professor Don Cleveland (a world leader in ALS research) at The University of California, San Diego. Lucie had worked on Alzheimer’s and tau (a microtubule associated protein cloned by Dr. Cleveland) during her PhD and was invited to work in Cleveland’s lab during her doctorate work; however, by the time Dr. Bruijn had made it to the Cleveland lab as a postdoctoral fellow, a direction of a different nature to tau had materialized: mutant SOD1 linked to familial ALS.

“The discovery of muations in SOD1 linked to familial ALS was huge,” Bruijn tells me. “Having a gene identified suddenly made it possible to study ALS in a whole new way. With SOD1 we could build animal models, we could manipulate it to see what might happen in cell culture – it was the first discovery of its kind for ALS. Because of that excitement, the obvious direction in Don’s lab was to develop the mouse models for the disease.” These mouse models ultimately showed that whatever the nature of mutant SOD1’s role in ALS, it was because of a novel gain of function of this protein and not because of a loss or up-regulation – this became significant later when thinking about potential therapies targeting SOD1.

After her time with the Cleveland group, and leading a group at Bristol Myers Squibb to develop model systems for neurodegeneration, Bruijn was approached by The ALS Association for the role of Vice President of Research there.

“I loved my position at Bristol Myers Squibb, but after agreeing (eventually) to interview with The ALS Association, I realized that the position offered provided me with a great opportunity to make a significant contribution in the field.  My strengths are to build teams and foster collaborations around particular research endeavors and I do not necessarily need to be directly involved in making the big discovery. I felt I could make a broader impact using both my academic and industry experiences. This was part of my reason to join The Association – and I’ve been there nearly 11 years.”

TREAT ALS

Throughout her time with The ALS Association, Bruijn has always been focused on the translational research of ALS-related discoveries, so much so she set up the initiative TREAT ALS (Translational Research Advancing Therapy for ALS) early after joining. “TREAT ALS was in thinking for a couple of years before it became a program. Coming from industry I was very used to the concept of drug development, the rigour and focus and the various stages involved. The sense was that academics had been good at bringing ideas and targets to the table, but there was a real gap in getting these from the academics into the pipeline for drug discovery.” Bruijn helped change that, and was particularily motivated as a result of a partnership with the National Institute of Neurological Disorders and Stroke (NINDS) to screen 1040 FDA approved-compounds in models of Huntington’s, Parkinson’s and ALS.  “I think that coincided with an increasing interest in the academic sector to become engaged in translational studies. With my expertise in industry and with my connections in academia, The Association was in now in a better place to think about translational work and that we should really gear our programs towards that.” – And so, TREAT ALS came into being.

Developing an ALS treatment

The opportunity to facilitate the development of a treatment for SOD1 through funding a partnership between academia and industry has been a particular highlight for Bruijn during her time at The ALS Association. “The thrill for me was being involved academically; in Don’s lab building the SOD1 mouse models, being in industry to really see what goes on there and setting up Association funding for Don’s group to nurture the lab’s partnership with a San Diego-based company, ISIS Pharmaceuticals. Don made a connection with ISIS and a potential ALS treatment; though ISIS had never tackled a neurological disease with its antisense oligonucleotide technology before, the concept was to use this technology to block production of the SOD1, and, therefore, its pathological effects – it has the potential to be a very effective therapy…”

“ISIS, in partnership with Don, tested the antisense technology in rat ALS models and saw significant success in the antisense treatment concept.” – It was reported in the Journal of Clinical Investigation that the treatment had prolonged survival in the rats.

Building on the ISIS success the rest of the preclinical work was funded through the TREAT ALS program and now the drug has phase I clinical trials status . The drug is currently being tested for safety in ALS patient volunteers and has so far been a success. “We know it’s safe. We don’t yet know what it will do clinically; we hope it will have an effect.”

It seems the partnership with ISIS offers many FALS patients substantial hope – but these patients may not be the only ones to benefit from such an enterprise. “With ISIS it has been a very interesting, mutually successful partnership. Another highlight is that now, because of the ISIS partnership, Huntington’s, spinal muscular atrophy (SMA) and myotonic dystrophy also have programs there.”

It’s complicated…

Developing cures for all patients of ALS however – despite the SOD1 work at ISIS – is not so straightforward, and Bruijn with TREAT ALS is also treading other research avenues in search of other therapies. These avenues have opened up very exciting possibilities in terms of potential ALS treatments; but first: Why is the situation with ALS so complicated?

To start with just 20% of FALS cases are caused by SOD1 mutations and the majority of ALS cases (about 90%) are actually sporadic with no apparent inheritance pattern. Reassuringly, mutations in several other genes have now been associated with ALS in both familial and sporadic cases. The list of ALS-associated genes is growing substantially and includes UBQ2, TDP-43 and FUS, and more recently C9ORF72 on chromosome 9. “If we imagine the ALS pie chart, it’s great to see the pie getting so well filled; for familial ALS it’s now over 50% full, maybe more likely 60%, so we’ve definitely got a smaller chunk to find – that forms part of our ongoing focus.”

An unpredictable disease

An extra difficulty lies in the unpredictability of the disease: no two cases of ALS are the same. “It’s a real spectrum,” Bruijn informs me, “ALS is a complex disease and there are going to be patients that have different onset patterns, those that have slow progression versus those with very fast progression. It’s interesting to note that within the SOD gene mutations,” – and over 150 have been identified to date – “There aren’t any that predict where ALS will begin in a patient; you can’t predict the onset pattern using a patient’s genetics.”

A number of the ALS-associated genes listed above have also been linked to the distinct but overlapping disease set of frontotemporal dementias (FTDs). “Another important component of the disease is that it can also be associated with FTD. There’s an overlap creating another spectrum – you can have pure ALS, you can have ALS and FTD or you can have FTD on its own.”

Faulty RNA metabolism: A common mechanism?

But with so many separate causes, are we not looking at a collection of diseases? “We hope some common pathways tie these multiple causes together – it’s important not to segregate a rare disease too much – and it is interesting that there are emerging themes hinting at a common mechanism:such as abnormal protein and RNA metabolism.” She then adds, “RNA metabolism in particular, because of TDP-43 and FUS, and now chromosome 9.” – Which we’ll get to later.

Going global

The diversity of ALS is one reason why familial studies and ALS registries have been vital to forwarding its research. Global collaborations are absolutely fundamental for such studies and nurturing this area is a focus for Bruijn and TREAT ALS; in fact ALS Association funding and collaboration-building was key to enabling the work on chromosome 9…” We funded several teams – with investigators all over the world.”

In general, any such enterprise has to be: “Totally international,” Bruijn states, “One reason for that is because [ALS] is a rare disease. If you want sufficient samples you have to be collaborative worldwide – the sample sizes need to be additive, especially for the genome-wide association studies. We had a big consortium to get the sample numbers up worldwide.” Indeed, the chromosome 9 finding results from the work of over 60 different scientists based at over 37 institutions worldwide using the DNA of Finnish, Italian and Welsh ALS patient cohorts amongst several others. The work was published this September in Neuron and also features our video interviewee Dr. Stuart Pickering-Brown.

A new focus: Chromosome 9

Because of the breadth of the chromosome 9 studies, the ALS community can say with confidence that they have identified the most common genetic defect associated with ALS to date: Over one third of all familial ALS patients carry a specific defect in the C9ORF72 gene located on chromosome 9. What’s more is the studies found up to 7% of sporadic ALS cases also carry the faulty gene. It is in early stages and the numbers of sporadic patients linked to the mutation may vary.  The fault within ALS-C9ORF72 is an abnormal number of repeats of the code ‘GGGGCC’ in a non-coding region of the gene – up to 1600 repeats of the code have been found at this location in some test subjects. Bruijn says the chromosome 9 work was, “Really quite a long haul. A challenge was juggling the dynamics of three separate ALSA-funded  initiatives with the same goal and keeping everyone’s confidence up. Investigators had committed their research effort to this for many years and the association had been involved with the various groups for over 7 years; it was very gratifying to eventually come to a conclusion.”

Chromosome 9 will soon go global in a different way – it is such a hot topic in ALS research. In fact it’s so new, it will hardly feature on the agenda at this year’s SFN Meeting; instead Bruijn is heading a closed strategic meeting there with leading ALS experts to discuss translating the C9ORF72 gene findings into a treatment as soon as possible.

“Everything will be done in parallel,” Bruijn says, hinting at the plans she has in mind, “The mouse model development, the antibody development; answering questions such as, why FTD sometimes? Why ALS another time? Why the same repeats are also found in sporadic patients? Genetic testing of patients: how do we communicate to families where it’s now present in sporadic form? Is it going to become hereditary in these cases? As with SOD1 in the 90’s, there is now a wealth of questions surrounding chromosome 9.” And it seems the approach may also parallel that taken with SOD1…

Clinical translation: It’s a parallel Universe

“We’re going to run the investigations in parallel; we don’t want to wait 13 or 14 years to understand the mechanism when perhaps we don’t need to. We might still block the effects of the abnormality without that knowledge – which is what we did with SOD.”

After talking with Bruijn, I predict that taking C9ORF72 from gene-of-interest to therapy-target might actually be quicker than with SOD1. The ALS Association, largely through Bruijn’s work, has a lot of building blocks already laid out this time. Take the pioneering clinical trials network supported by TREAT ALS for example the North East ALS Consortium (NEALS); through working with the consortia of ALS clinical centers in the US, The ALS community is well poised to collaborate with Industry and take new compounds forward into trials – in fact efforts to build clinical networks are ongoing in close collaboration with the US.

What lies ahead…

What is so exciting about the next step with chromosome 9 research, however, is that not only has the field advanced significantly in their ability to develop appropriate model systems since SOD1, there are other neurological disorders  linked to abnormally expanded repeats that serve to inform the ALS field. There  may now be a way to approach therapy development by targeting the expanded ‘GGGGCC’ repeat region, taking lessons from the antisense drug development for SOD1. This could be done even prior to understanding the exact mechanisms of C9ORF72′s mutations in the disease. The clue lies in the common mechanisms mentioned earlier –  aberrant RNA metabolism and abnormal protein handling.

Concluding, Bruijn remarks, “It’s an interesting time to be in ALS research – It’s explosive.”

Article by @DebGrainger

This article was  revised by the author at 23:17 GMT, 11/10/2011