Thursday, January 28, 2016

Rare Diseases: High Priority in Precision Medicine

It is very difficult to steer medical scientists away from their belief that common diseases are more important than rare diseases. Too often, scientists are persuaded by the observation that a few dozen common diseases account for the vast majority of the morbidity and mortality suffered by humans. Hence, a breakthrough in treating any of the common diseases will benefit many more people than an advance in any of the rare diseases. The reasoning seems flawless, but research targeted at the common diseases has been disappointing. In the past 50 years, most of the major advances in medicine have involved the rare diseases. Advances in the common diseases have come about as a consequence of discoveries made on rare diseases.

As it happens, the rare diseases are much easier to understand and treat than the common diseases. If we waited for medical scientists to cure the common diseases, we would miss our currently available opportunity to cure diseases, either rare or common.

Rule - Rare diseases are easier to treat than common diseases.

Brief Rationale - Rare diseases have simple genetic defects, have little heterogeneity, and have few metabolic options with which they can evade targeted treatments.

Ryanodine receptor 2 mutations are responsible for several rare arrhythmia syndromes in humans (e.g., forms of catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia) Individuals with these disorders can be treated with drugs that stabilize the receptor. Damage to ryanodine receptor 2 seems to occur as a component of common heart failure; leading to calcium leak and arrhythmia. Preliminary studies indicate that drugs that stabilize the receptor may ameliorate all types of heart failure and the lethal arrhythmias that ensue (2). Thus, our deep understanding of a rare disease had led us to a general understanding of a common disease.

Alexion is a pharmaceutical company that specializes in developing drugs intended to treat rare diseases. For example, Alexion discovered and developed Eculizumab (trade name Soliris), a first-in-class terminal complement inhibitor. Eculizumab was approved by the FDA in 2007 for the treatment of paroxysmal nocturnal hematuria; and in 2011 for the treatment of atypical hemolytic uremic syndrome. Subsequently, eculizumab was tested for its effectiveness for several common diseases. Eculizumab was a candidate treatment for so-called dry age-related macular degeneration, a common disease; though it was not shown to be effective (3). On the brighter side, eculizumab has been shown to prevent acute and chronic rejection in certain subsets of patients who received renal transplants (4). When you have a drug that is known to target a particular member of an active physiologic pathway, it is likely to have some benefit in one or more common diseases whose clinical phenotype is due, in part, to aberrations of the same pathway.

Rule - Dugs that are safe and effective against rare diseases will be used in the treatment of one or more common diseases.

Brief Rationale - The rare diseases, as an aggregate group, comprise every possible pathogenic pathway available to cells. Hence, pathogenic pathways that are active in the common diseases will be active in one or more rare diseases. Agents that target pathways in the rare diseases are candidate treatments for the common diseases with which they share active pathways.

Wrinkled skin is one of the most common physical conditions. Every man and woman who lives long enough will wrinkle a bit. For some individuals, wrinkling is problem that merits medical attention. Botox (botulism toxin) is the drug du jour for treating wrinkles. Botox is also one of the most powerful poisons known. How did it come about that Botox emerged as a popular wrinkle treatment? Botox was original developed, tested, and approved to treat several rare diseases characerized by uncontrolled blinking. After approval was awarded, botox was found to be extremely effective for rare spasmodic conditions, including spasmodic torticollis (i.e. wry neck). In the course of treating rare diseases, it was noticed that Botox injections could temporarily erase wrinkles. The rest is history. The Botox story exemplifies how an effective treatment developed for a rare diseases can gain popularity as a treatment for a common conditions.

Rule - It is much more useful to treat a disease pathway than it is to treat the individual gene mutation or its expressed protein.

Brief Rationale - Many different diseases may respond to a drug that targets a pathogenic pathway, while only one genetic variant of one rare disease is likely to respond to a drug that targets the disease-causing gene or its expressed protein.

There is a very important lesson to be learned: Treat the pathway, not the gene. This lesson is somewhat counter-intuitive and is received with some skepticism from experienced medical researchers. Nonetheless, it is a core principal that diseases are caused by perturbed pathways, and that the successful treatment of diseases have always involved compensating, in one way or another, for pathway disturbances. Let us review some examples that demonstrate the point.

Imatinib (trade name Gleevec) inhibits tyrosine kinase, an enzyme involved in a pathway that drives the growth of various rare tumors and proliferative diseases (e.g., chronic myelogenous leukemia, gastrointestinal stromal tumor, hypereosinophilic syndrome) (5), (6), (7), (8), (9). Pathways with increased tyrosine kinase activity, and pathways whose tyrosine kinase activity is particularly sensitive to the inhibiting action of imatinib would make the best drug targets. Because Imatinib is targeted to a key protein in a general pathway that contributes to a proliferative phenotype, it has potential benefit in diseases caused by mutations in genes other than tyrosine kinase.

Bevacizumab, trade name Avastin, is an angiogenesis (i.e., vessel-forming) inhibitor (See Glossary item, Angiogenesis). All cancers require vessel growth. In theory, bevacizumab is a universal tumor growth inhibitor because its target is the non-neoplastic mesenchymal cells that form the vessels that feed growing tumor cells. Bevacizumab is employed in the treatment of common cancers, including cancers of the colon, lung, breast, kidney, ovaries, and brain (i.e., glioblastoma). Bevacizumab produces tumor shrinkage in more than half of vestibular schwannomas occurring in Neurofibromatosis 2 (10). As you might expect, Bevacizumab has its greatest value in diseases for which neovascularization has a required role in pathogenesis. Two non-cancerous diseases of vascularization, treated with angiogenesis inhibitors, are hereditary hemorrhagic telangiectasia (11), and various forms of ocular neovascularization, including common age-related macular degeneration (12).

Because pathways are interconnected, a drug that is effective against a component of a pleiotrophic pathway may be effective against multiple diseases. For example, Janus Kinase genes (e.g., AK1, JAK2, JAK3, TYK2) influence the growth and immune responsiveness in various blood cells, through their activity on cytokines. Mutations of the JAK2 gene are involved in several myeloproliferative conditions, including myelofibrosis, polycythemia vera, and at least one form of hereditary thrombocythemia (13), (14), (15).

Inhibitors of JAK genes have been approved for the treatment of various diseases that involve heightened proliferation of lymphocytes, in immune reactions, or blood cells, in myeloproliferative disorders. Ruxolitinib has been approved, in the U.S. for use in psoriasis, myelofibrois and rheumatoid arthritis (16). A host of JAK pathway inhibitors are either approved or under clinical trials for the treatment of allergic diseases, rheumatoid arthritis, psoriasis, myelofibrosis, myeloproliferative disorders, acute myeloid leukemia, and relapsed lymphoma (17). Again, specialized knowledge of rare diseases had led to generalized methods of treating a variety of related diseases, some of which are quite common.

Rule - Common diseases and rare diseases that share a pathway are likely to respond to the same pathway-targeted drug.

Brief Rationale - Pathogenesis (i.e., the biological steps that lead to disease) and clinical phenotype (i.e., the biological features that characterize a disease) are determined by cellular pathways. If a pathway has a crucial role in the development of disease, then you would have reason to hope that drugs that disrupt the pathway will alter the progression and the expression of the disease, whether the disease is common or rare.

Individuals with a rare resistance to HIV infection have a specific deletion in the gene that codes for the CCR5 co-receptor. The gene plays a role in the entry of HIV into cells; no entry, no infection. As it happens, both HIV virus and smallpox virus enhance their infectivity by exploiting a receptor, CCR5, on the surface of white blood cells. This shared mode of infection may contribute to the cross-protection against HIV that seems to come from smallpox vaccine. It has been suggested that the emergence of HIV in the 1980s may have resulted, in part, from the cessation of smallpox vaccinations in the late 1970s (18). The same, rare CCR5 gene deletion that protects against HIV infection may very well protect against smallpox infection. We may never know with certainty whether this is true because smallpox has been eradicated, along with smallpox experiments. Nonetheless, knowledge of the role of CCR5 in HIV infection has inspired the development of a new class of HIV drugs targeted against entry receptors (19).

Individuals with genetic absence of Duffy antigen receptor for chemokines (i.e., DARC, formerly known as Duffy blood group antigen) are protected from malaria cased by Plasmodium vivax. It turns out that entry of the parasite requires participation by DARC (20), (21). A new vaccine candidate for P. vivax malaria, targeted against the Duffy binding protein was developed based on observations of naturally occurring resistance in individuals lacking DARC (22), (20).

Osteoporosis-pseudoglioma syndrome is a rare disease characterized clinically by multiple bone fractures and various eye and neurologic abnormalities. It is caused by loss-of-function mutations in the low-density lipoprotein receptor-related protein-5 (LRP5). LRP5, under normal conditions, reduces the production of serotonin in the gut. Based on rare disease research directed towards understanding the role of LRP5, agents that compensate for the reduction in LRP5 by reducing gut serotonin are candidate drugs for the treatment of both rare osteoporosis-pseudoglioma syndrome, and common osteoporosis (23) (24), (25).

Of course, advances in the common diseases may have value in treating rare diseases. Losartan is an effective drug against one of the most common diseases of humans: hypertension. Losartan blocks the angiotensin II type 1 receptor, and it also blocks TGF-alpha (Transforming Growth Factor-alpha). In Marfan syndrome, a rare disease of connective tissue, growth of the aortic root may lead to life-threatening aortic aneurysm. A reduction in TGF-alpha activity, following losartan treatment, reduces growth of the aortic root, and slows the progression of aortic root distension in Marfan syndrome (26).

Shared cures for the rare diseases and the common diseases do not occur as low-probability events in an unpredictable world. Knowledge of disease biology leads us to conclude that whenever a cure for a rare disease is found, there is a high likelihood that this same cure will have practical application in the treatment of a common disease. Pharmaceutical companies understand that rare disease research and common disease research is often the prelude to common disease research (27).

It is crucially important to appreciate the role of rare diseases in drug development. If funding agencies do not appreciate how cures for the rare diseases will lead to cures for the common diseases, the field of rare disease research will continue to be under-funded and generally ignored by the medical research community.


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[27] Ayme S, Hivert V (eds.), "Report on rare disease research, its determinants in Europe and the way forward", INSERM, May 2011. Available from:, viewed February 26, 2013.

- Jules Berman (copyrighted material)

key words: rare diseases, orphan drugs, precision medicine, medical research, research funding, justification for medical research, jules j berman