RARE DISEASES AND GENETIC RESEARCH

Dr Anne Pariser: The overwhelming majority of rare diseases are single gene disorders – or monogenic disorders – where there’s a mutation in just one gene and sometimes as little as one base pair within the gene. If you can find the mutation in the gene, and then work backwards to find out what that gene does, what it transcribes, that gives us a target (to work towards). If we have a target to go after, we can design drugs, or genetic or other advanced therapeutics with considerable precision to go right after whatever that problem is. The vast majority of modern drug development is using this targeting strategy, so in addition to changing how we approach drug development, it also opens up the possibility of personalised medicine, and we’re starting to see some examples of this. 1

A lot of rare disease patients go through what we call the diagnostic odyssey; it often takes years to get an appropriate diagnosis. Now it’s a lot easier and less expensive to do genomic analysis.

In England, for example, with the 100,000 Genomes Project, they’re trying to move more rapidly towards characterising young children and sick babies in the NICU to try to make these diagnoses earlier. Once you know what’s wrong, it opens the possibility of trying to develop targeted therapies that could be both highly efficacious, but also improve the safety of the drugs, because now you’re only treating a selected subset of patients who are likely to respond.

It is hard to find rare disease patients and it can be very hard to diagnose patients. We know there are a lot of people out there who aren’t diagnosed. This is probably an underestimation, but here in the US we estimate about 25 to 30 million patients have a rare disease. That’s about one in 10 people, but it may actually be higher than that because there’s so many people that haven’t been diagnosed, and that percentage should be similar pretty much anywhere you would look around the world. These estimates are derived from some genomic studies based on what we know about diseases. We just published a paper on a project called ‘The Ideas Initiative’, where we were trying to do a pilot to estimate the cost burden of rare diseases, with cost being a surrogate for illness. People who are high users of a medical system tend to have serious illnesses. That’s not a huge surprise, but you can quantify costs, and it’s a lot more difficult to quantify pain and suffering. It is very difficult to even find rare disease patients in medical records or health system databases. The majority of rare diseases – probably about 75% – don’t have a specific medical record code. About 50% don’t even have a general code, so they’re often lumped into these very high level terms like ‘congenital anomaly unspecified’, ‘seizure disorder’, or ‘unspecified motor delay’. About one in ten people have rare diseases illnesses, and that’s a large public health problem which hasn’t really been identified. It also hasn’t been prioritised, and this leads to all kinds of downstream effects: difficulty getting appropriate care, and difficulty even telling people what they have. And 95% of rare diseases don’t have a treatment. Has this footprint changed over the past five years? Probably not, because these patients have always been there. I think our ability to recognise this now and try to call attention to it has been increasing.

I can only really speak from the US perspective; we have a very fragmented healthcare system. You add a serious illness – for which there are a few disease experts or expert centres to care for these patients – to the existing problems with fragmented care, lack of coverage, out of pocket expenses. People who don’t live in urban centres will need to be treated at a tertiary care centre or a super specialist, and there may only be a couple for each disease in the country, so they’re often having to travel long distance to access care. We suspect that it may take longer to get a diagnosis if you’re in a rural area, or in a place that does not have access to a medical expert. Think of any problem in a healthcare system, and then throw a rare disease on top of that, and it just makes it worse.

First and foremost, we must recognise rare diseases for the serious public health problem that they are. We have the rare diseases as a misnomer; collectively, they’re not rare at all. We are trying to educate people that rare diseases are rather common – not the individual diseases, but the patients with rare diseases. They have serious illnesses and need better care, and are as entitled to research and medical care and efficacious therapies as anyone else. That’s a real priority. We have the tools to improve this diagnostic odyssey, and we have the capability to do it now. What we’re trying to do, through education, is move on that faster. A lot of these diseases are slow, chronic, and progressive. For example, a child may have a delay, maybe not quite meeting their milestones. The tendency is to check again in six months, check again in a year, and this really starts to add up to years and multiple referrals. What we’re trying to do is try to escalate, particularly, our younger patients faster to get genetic testing, and preferably at an expert centre, or children’s hospital that is used to handling these diseases. Most of our diseases don’t have approved treatments, we know there are 1000s of diseases right now – we know the gene, and we know how to at least potentially treat that patient (a gene replacement, a gene silencing, or something that modulates the gene expression). We have the technology to do a lot of this for many more diseases; we now face more operational, logistical issues.

This is predominantly now a translational problem. Once a person is appropriately diagnosed, it’s then trying to string all the pieces together to use some of the things we already know how to do. That can mean trying to speed up gene therapy development, for example. It’s the same for newer technologies, such as antisense oligonucleotides and gene editing. We estimate that it’s going to take about 2,000 years to get everybody an effective therapy at the rate we are going now. Can we approach this by looking at many diseases at the same time?

We’ve started a programme at NCATS called Platform Vector Gene Therapy (PaVe-GT) where we’re trying to develop four gene therapies at the same time.2The AAV gene therapy is a natural platform; you have the capsid of the virus, hollow out the virus DNA, and put in the human gene of interest. This hopefully will save time, money, and resources, and we can learn from one programme to another. Hopefully, that could set us up well enough that we wouldn’t have to keep repeating a lot of these steps, but we could just move a lot faster. The NIH also just stood up what they’re calling the Bespoke Gene Therapy Consortium, which is examining the commonalities around gene therapy development in the preclinical area and the clinical areas. 3 We can do these one at a time or share the knowledge from one programme to another. Gene editing and antisense oligonucleotides also have that potential as well. Oncology has done quite well in advancing therapeutics through platform approaches, and we’re trying to borrow from their experience with platforms, as well as treating multiple diseases or multiple drugs within a single protocol. We think translational science is the answer to this, so we just need more of it.

Almost all of them are neglected to some degree. We only have therapies for about 5% of rare diseases, so there are 95% to go. Most of these diseases are sometimes referred to as the ‘Ultra-rare Disorders’. That’s not a real definition; it’s rare or it’s not, and in this country, it’s less than 200,000 people with the disease in the US. In Europe, it’s a prevalence estimate of five per 10,000 people with the disease.4 For most rare diseases, they will be classified as rare in either region, because 90% of the rare diseases are what would fall into this ultra-rare category (approximately one in a million or so people with the disease or less). We have lots of diseases, where there’s 100 or fewer patients, or a few thousand or fewer. The real distinction is it’s very hard, even with available financial incentives, to make a business case to develop a drug for 50 people or so. Even when we know what’s wrong, it is trying to harness resources to bring it through a drug development programme, so we really need better solutions.