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The mutual benefits of rare disease research and precision medicine by Deborah Grainger, Ph.D “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease.” British Physician William Harvey, 1657 P recision medicine seems tailored to the study of rare diseases: at least 80 percent of them arise from genetic variations, and (though not always the case) show varying degrees of heterogeneity from patient to patient. They also represent a moderately untapped source of genomic ‘big data’, due to most being studied by only a handful of specialists worldwide. Now, many scientific establish- ments are recognizing the value of combining rare disease research data — not only for their collective potential to alleviate individual patient suffering, but as lenses to examine the more common diseases of man. In modern research climates, where there is much emphasis on return of interest (ROI), a tendency to view rare disease research as beneficial to only a handful of individuals has endured. By definition, a rare disease is one that affects under 200,000 people in the United States, or under 5 in every 10,000 individuals in Europe. Given these numbers, it is easy to see why the classic, intractable logic predominates that fewer patients equal fewer global benefits — but is this prevailing logic inherently flawed? 10

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The mutual benefits of rare disease research and precision medicine by Deborah Grainger, Ph.D

“Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten paths; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by careful investigation of cases of rarer forms of disease.” British Physician William Harvey, 1657

P recision medicine seems tailored to

the study of rare diseases: at least

80 percent of them arise from

genetic variations, and (though not

always the case) show varying degrees

of heterogeneity from patient to patient. They

also represent a moderately untapped source

of genomic ‘big data’, due to most being

studied by only a handful of specialists

worldwide. Now, many scientific establish-

ments are recognizing the value of combining

rare disease research data — not only for

their collective potential to alleviate individual

patient suffering, but as lenses to examine

the more common diseases of man.

In modern research climates, where there is

much emphasis on return of interest (ROI),

a tendency to view rare disease research as

beneficial to only a handful of individuals

has endured. By definition, a rare disease is

one that affects under 200,000 people in

the United States, or under 5 in every 10,000

individuals in Europe. Given these numbers, it

is easy to see why the classic, intractable logic

predominates that fewer patients equal fewer

global benefits — but is this prevailing logic

inherently flawed?

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Deborah Grainger, Ph.D, is an independent science

writer with a wide-ranging subject interest. Equally

comfortable covering topics from complex neuroscience

to drug combinations in immune oncology, she honed

her writing skills working in communications for five years

at a biotechnology SME. Deborah also holds a PhD in cell

signaling from the University of Manchester.

Looking at the bigger picture helps to broach

potential answers to such a question… There

are around 7,000 known rare diseases meaning

that, in total, around 30 million Americans and

a similar number of Europeans live with one of

these conditions ‘making rare disease patients

paradoxically common’. In fact, it is estimated

that around 400 million people throughout the

world suffer with a rare disease1, meaning the

collective disease burden of these conditions is

comparable to more well-known counterparts.

Admittedly, rare diseases vary more in terms

of symptoms, severity, and prognoses than

major diseases such as cancer, but precision

medicine is a great leveler; because of its

approaches, we now understand that most

cancers are as individual as their hosts —

even those of the same type and stage show

this variance. Yet, we still appreciate the

translational benefits of studying cancers

across the board, whilst simultaneously racing

to identify more stratified treatments for them.

The predominantly genetic nature of rare

diseases, plus new technologies such as

CRISPR-Cas9 gene editing, surely open up

similar translational potential between remote

diseases. Once one successful gene therapy

becomes established, has a precedent not

been set?

Perhaps the most compelling testament of

the value of rare disease research though,

especially in the context of counterbalancing

a ROI-centered argument, is its past triumphs

in wider knowledge acquisition. Ground gained

in the research of a surprising number of rare

diseases has uncovered some of the inner-most

workings of the more common ones.

The study of Tangier disease for example—an

extremely rare disease manifested by severe

perturbations in cholesterol metabolism—may

have identified a therapeutic target for mitigating

the risk of heart disease: a receptor protein

encoded by the ABCA1 gene. This protein

interacts with the apoA-1 protein to clear

excess cholesterol from the cell interior in

the form of HDL (good cholesterol) for

removal by the liver (2). Furthermore, it

performs this same task in the brain, but

instead binding a protein called ApoE—thus

playing a role in the removal of amyloid-beta

and, therefore, provides insight into

Alzheimer’s disease3.

Other notable examples include Liddle

syndrome (a rare kidney disorder) and its

contribution of knowledge on the pathology

of hypertension4 and Fanconi anemia, which

has shed light on the intimate relationship

between genetic instability and cancer (plus

mechanisms of bone marrow failure

and resistance to chemotherapy)5,6.

More recently, the fatal disease Niemann-Pick

Type C (NPC), has even helped us to under-

stand how Ebola spreads throughout the body

— the link being that the Ebola virus uses the

NPC1 protein made by the gene to gain entry

to the cell and replicate7. Mice that only have

one normal copy of the NPC gene — simulating

carriers of the disease — have much higher

Ebola survival rates8. From the outset, would

anyone have made this connection?

As the NPC-Ebola association demonstrates,

scientific discoveries rarely start out at point

‘A’ and work directly to ‘B’ in a linear fashion.

They normally get there via a handful of other

letters (perhaps via ‘Z’, ‘F’ and ‘Q’ in the

process). Widening the net to capture the

entire alphabet and working to identify the

unpredictable,by tracing emerging patterns

is a smart strategy — especially if you have

optimized, automated processes available to

do so. This approach has been adopted by

research organizations like Genomics England,

which in 2014 got its 100,000 Genomes Project

underway in a bid to sequence patient

genomes to understand rare diseases better.

With more budgets being set aside for

precision medicine, such as the $215 million

recently dedicated by the US Government to

the National Institute of Health’s Precision

Medicine Initiative Cohort Program, it is only

a matter of time before precision medicine

enables more rare disease research success

stories. Successes such as the repurposing

of a failed cancer drug in the treatment of

premature aging condition Hutchinson-Gilford

Progeria Syndrome9— enabled by the

landmark Human Genome Project and the

identification of progeria’s underlying genetic

causes.

Spurred on further by additional innovations

in genomics, the falling cost of whole genome

sequencing and data collection and sharing, the

rare conditions that have borne the ‘orphan

disease’ label for so long may yet reveal the

secrets to some of Nature’s most unyielding

mysteries. Fewer patients equal fewer global

benefits? This old, persistent logic is, most

likely, deeply flawed.

References

1. de Vrueh, Baekelandt, de Haan, WHO. Priority Medicines for Europe and the World 2013 Update, Background Paper 6.19 Rare Diseases [Internet]. Priority Medicines for Europe and the World 2013 Update. 2013 [cited 2016 Feb 21]. Available from: http://www.who.int/medicines/areas/priority_medicines/Ch6_19Rare.pdf2. DeLude C. One Island’s Treasure | Proto Magazine. 2009 [cited 2016 Feb 22]. Available from: http://pro-tomag.com/articles/tangier-disease-one-islands-treasure3. Yassine HN, Feng Q, Chiang J, Petrosspour LM, Fonteh AN, Chui HC, et al. ABCA1-Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheim-er’s Disease. Journal of the American Heart Association. 2016 Feb 12;5(2). 4. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001 Feb 23;104(4):545–556. 5. Schroeder-Kurth T. Why, What and How Can We Learn from a Rare Disease Like Fanconi Anemia? In: Schindler D, Hoehn H, editors. Fanconi Anemia. Basel: KARGER; 2007. p. 1–8. 6. D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010 May 20;362(20):1909–1919. 7. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011 Sep 15;477(7364):340–343. 8. Herbert AS, Davidson C, Kuehne AI, Bakken R, Brai-gen SZ, Gunn KE, et al. Niemann-pick C1 is essential for ebolavirus replication and pathogenesis in vivo. MBio. 2015 May 26;6(3):e00565–e00515. 9. Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, et al. Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666–16671.

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