This last academic year I set my 1st Year Pharmacy Technician PT students a research task. This is really quite unprecedented because, even in final 4th year, only a subset of our students are able to carry out a research project with literature review. The PT1 research task was more of a literature review but each one was requested and required to find out about a particular lysosome storage disorder. They did really well and at the end of the year I told our external examiner that I'd be giving more such tasks in future. Our students are often bad at recalling information in the May exams, so why not have them work to discover something in October and January. I'll bet they'll retain that hard-won auto-didactic information longer.
I am, therefore, a bit primed for lysosomes and lysosome storage disorders or LSDs, so was delighted to find a fine supplement on LSDs in Nature from last September. The information appears to be outside the Nature paywall, so you can read a helluva lot about LSDs, their tragic effects, the robust advocacy of parents, the beginnings of therapeutic success and the economics of rare diseases. I'm not going to give you a synopsis but rather focus on a couple of interesting nuggets.
There are about 50 known and named defects in the inventory of the lysosome. The inventory consists of enzymes which break-down worn-out components of the cell. Because some poor wee mite presents with a really weird set of symptoms, doctors and genomic researchers have been able to reveal the existence of a normally present enzyme which is banjaxed in that child. You don't have to know the molecular basis of a disease to perform a diagnosis and implement a protocol for reducing its incidence - Waren Tay first noted a characteristic symptom of Tay-Sachs in the 1880s - but it sure helps. The protocol that worked for Tay-Sachs was no therapy but a battery of methods for preventing the birth of kids with the lesion. Knowing the molecular fundamentals is key to developing a therapy.
A nice infographic in the Nature LSD supplement bins potential therapies (oh oh a list, I feel an exam question coming on):
- gene replacement therapy
- This is the Holy Grail. genes make enzymes, so if you can sort out the genetic defect you can make as much enzyme as you need. The gene is buried in the nucleus of the 100 trillion cells we each possess, split into exons and we know only a little about how and when and where it is switched on. Delivery and implementation are both huge problems currently.
- enzyme replacement therapy ERT
- This is the current cutting edge. Lots of pharma companies, big and wannabe big, are developing molecules that can be taken by patients and get delivered to cells, absorbed by them and thereafter popped into the lysosomes and get going on the enzymatic breakdown and recycling process. There are 100 trillion cells in there, each with 50 -1000 lysosomes which are constantly being turned-over. It strikes me as being amazingly confident that a company would embark on such a mighty distribution problem. It's a lot harder than that faced by Amazon or FedEx!
- enzyme refolding therapy by chaperones
- for some of the 50+ LSDs, the gene is there and the enzyme is almost there but it just comes off the assembly-line a bit bent out of shape. Broken and defective proteins get tagged for recycling and delivered, with some irony, to the lysosome . . . but to the loading dock rather than the executive entrance. Chaperones aka Heat Shock Proteins HSPs are tasked to primp up some normal enzymes (only a minority of proteins fold spontaneously as they come out of the ribosome). Entrepreneurs are asking if they can make or modify a chaperone to push a defective lysosomal enzyme into shape.
- substrate reduction therapy SRT
- Gaucher's Disease GD, one of the commoner LSDs is caused by the accumulation of glucocerebroside aka glucosylceramide aka sphingolipid in cells because glucocerebrosidease, the enzyme that breaks it down, is defective or missing. We need sphingolipid and quite a lot of it, but like many good things (carrots, alcohol, cream-cakes) too much is toxic. If we could limit the amount of sphingolipids produced then the lysosome wouldn't get overwhelmed. That's the idea aNNyway.
Hard enough? Just one more point. The problem with developing novel molecular therapies is that, with the idea, the experiments, the false leads, the dead ends, the replications, the validation, the clinical trials phases I, II and III, the licencing . . . it costs the bones of $1 billion to bring a new drug to market. All new drugs are developed on a For Profit basis and a great many entrepreneurs / capitalists have taken a risk on the venture: they want a return on their investment, so the costs and the profit must be amortised over the market so that the debt can be paid off before the patent runs out - between 5 and 10 years. Some markets are cash cows: overweight, un-young, insured people will benefit a little from statins on prescription and there are LOT of punters in that category. So the cost per dose is small enough. But take a LSD like Niemann-Pick type C brought on by a defect in the NPC1 or NCP2 gene. That only occurs in 7 births in a million. That's about 30 cases in the USA and another 75 in the EU . . . and that's your market! Everyone avoids thinking about poor black babies with a broken NCP1: they couldn't afford the drugs no matter how cheap.
There is tantalisingly good news for these orphan diseases which nobody will own. It turns out that both Gaucher's Disease an LSD and Parkinson's have a genome wide association with having a mutated GBA1 gene. Parkinson's is about 600x more common in over 65s than Gaucher's is in under 1s. Nobody has found the mechanistic common ground on that association . . . yet. But if Gaucher's is a sort of early onset Parkinson's, like chicken pox is the childhood version of shingles, then the bigger market might encourage creative science that might have positive fall-out for Gaucher-mites.
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