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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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