ClinTrialFan

Hi Donovan! I have a slightly weird mix of questions: I work in a lab that does research into SMA, and I don't get many opportunities to talk to patients. I'm really curious about what (or if!) you think about the aspects of SMA treatment/research that form a big part of my life.

1) Are you aware of -- and do you engage with -- SMA patient communities / support groups like families of SMA or The Jennifer Trust? What sort of impact, if any, do they have on your life?

2) There are a couple of early-stage clinical trials going on, for example the ISIS trial based on RNAi and the AAV gene therapy trial out of the Nationwide Children's hospital. Had you heard of these? Are they interesting for you to follow along with, or do you prefer to wait until there's something that can actually help patients, or even you specifically?

3) Any new trial needs volunteers, who expose themselves to some risk and may never benefit from the treatment. This is especially true of the Phase I "safety" trials where doses are generally very low, and not expected to have an effect. (NB: patients do occasionally benefit from the low doses in a Phase I trial, but it's definitely not something to bank on). In the specific case of the gene therapy trial, being a part of this early "safety" trial means that you might never be able to be given the actual treatment at full dose, when (if!) it has been perfected. It's an incredibly brave and selfless act, and not something that I'm sure I'd have the stones to do myself. What are your feelings about clinical trials? If one came along that could help you, would you consider it? What about one that probably wouldn't help you, but might help future patients?

(NB: This last questions is totally speculative; I don't know of any trials in the works aimed at Type II patients. I'm not saying that there definitely aren't any, but I AM saying that I don't know about any)

Those questions are long and a bit involved, sorry! Like I said, my entire work day is spent thinking about SMA as a biological system, but I've only met a tiny handful of actual patients, and all very briefly. Hopefully my perspective doesn't come across as too weird as a result!

I will say though, that the SMA patients I met were pretty inspiring - amazingly upbeat and friendly, even to a lowly labrat like me. Thanks for the AMA!

Someone with Type 0 who's able to go to high school, seriously? Wow, Everything I'd read told me that type 0 patients don't normally survive much past birth. I know there are other factors, that's why SMN2 copy number doesn't prefectly predict severity. The only know protective factor that I'm aware of is Plastin 3 (PLS3), which can be protective in severe SMA patients, although I think that's only been observed in (pre-pubescent?) females in a couple of families. I can dig up some references on that if you're interested?

Explanation For non-specialists: Spinal Muscular Atrophy is caused by an inability to make the protein "Survival of Motor Neuron 1", aka SMN. Most of our SMN is made by the gene SMN1. Something like 1/40 people (it varies depending which researchers you believe and which population they're looking at, but 1/40 is about right) carry one bad copy of the gene, but also one good copy from the other parent. They're completely fine, because one functioning copy is enough.

Occasionally, two of these carriers meet and have kids. For each of these kids, there's a 1/4 chance that they'll end up with two crap copies of SMN1. This is something like 1/6000 live births (again, this figure varies depending who's counting, but it's about right). However, all is not lost! At some point in our evolutionary history, a chunk of the chromosome that contains SMN1 got duplicated, flipped around and stuck back in... so on that mirrored section of chromosome we have a second gene called SMN2. Now, SMN2 is almost identical to SMN1 but contains an error that means it's roughly 10% as good at producing the protein as SMN1 is. Interestingly, while we all just have one copy of SMN1 (well, one copy from each parent), different people have anywhere from 0 - 20ish copies of SMN2. So, if you're unlucky enough to miss out on inheriting a good copy of SMN1, you might have enough good copies of SMN2 to make up for it. 20 copies? You're golden, probably never realise you have the disease. As your number of copies of SMN2 goes down, your disease severity goes up. Kind of.

Weirdly, the number of copies of SMN2 you have doesn't perfectly predict your disease severity. So doctors can do a genetic test to see how many SMN2 copies you have and use that for a tentative diagnosis but, as I'd bet happened with OP, some patients do better than their SMN2 copy number would lead you to expect. However, Type 0 patients have no copies of SMN2; they're completely incapable of producing any SMN protein. This is generally lethal before birth or, rarely, shortly after. I am NOT a medical doctor, but everything I've read about the genetics of SMA means that it's hugely surprising for a Type 0 patient to make it to high school age, never mind be healthy enough to actually attend. That's awesome.

So, if we know from patients like this that SMN2 sopy number doesn't perfectly predict disease severity there must be other factors, possibly genetic. One of those factors is how much of a protein called Plastin 3 you produce; it's not totally understood why it helps, but it's definitely involved in some of the same processes as the SMN protein. At least a few labs around the world (including mine, although it's not the focus of my work) are racing to understand this, in the hope that it'll suggest another route of treatment for SMA patients.

Interesting, thanks!

Because I'm not a medical doctor, the only time I meet patients is through organisations like those. Which is always a great experience for me, but it does mean that I never get to encounter people who're not so into that. So thanks for the AMA, I really appreciate it!

Can I ask what you dislike about the MDA's direction? I have to admit I don't know much about them, particularly from a patient's perspective.

Thanks for the answers about the trials! My professional dream is to run a (successful!) trial of a treatment I've contributed to, and I read a lot of scientists' write-ups of trials, but patients' attitudes to them is something I don't have a good way of finding out about. So that's really fascinating to me.

As far as I know (with the important caveat that I am not a medical doctor, and so you shouldn't take my opinion too seriously), SMA types are still based on developmental milestones, as you described. Disease severity -- i.e. what type you have -- can be roughly predicted by looking at SMN2 copy number and so (some?) doctors will check that when SMA is first diagnosed, but patients sometimes defy those expectations. So assessment of symptoms is still the deciding factor.

It's not totally clear why some patients' symptoms turn out to be less severe than their SMN2 copy number would lead you to expect. There are indications that other genes are involved, e.g. PLS3 (which makes a protein that's involved in some of the same tasks as SMN within cells), but the picture is far from complete.