Tuesday, February 16, 2016

Remarkable Progress in the Rare Diseases

More than 2,000 genes have been linked to 2,000 rare diseases (1). In most cases, these links are presumed to be causal (i.e. mutations in the gene lead to the development of the disease). Virtually every gene known to cause a rare disease was discovered within the past half century. The diseases whose underlying causes were known, prior to about 1960, numbered in the hundreds, and the majority of these well-understood diseases were caused by infectious organisms (See Glossary item, Infectious disease).

Progress in the genetic diseases greatly accelerated in the 1960s, and the earliest advances came to the group of diseases known as inborn errors of metabolism. Treatments consisted of avoidance of substances that could not be metabolized in affected individuals (e.g. avoidance of phenylalanine in newborns with phenylketonuria, supplements of thyroid hormone in congenital hypothyroidism, avoidance of galactose in newborns with galactosemia, supplementation with biotin in newborns with biotinidase deficiency, specially formulated low protein diets for newborns with maple syrup urine disease, and so on).

Some of the ground-breaking advances in rare disease research include the 1956 discovery of the specific molecular alteration in hemoglobin that causes sickle cell disease (2), (3); and the identification of the cystic fibrosis gene in 1989 (4). In 2007, Leber congenital amaurosis, a form of inherited blindness, was the first disease to be treated, with some clinical improvement, using genetic engineering. The mutated RPE65 gene was replaced with a functioning gene (5). Partial vision was obtained, in individuals who were previously blind. It remains to seen whether genetic engineering will ever restore adequate and long-term vision to individuals with Leber congenital amaurosis (6). It is noteworthy that the test case was made on an extremely rare form of blindness, not a common form such as macular degeneration. The reasons why rare diseases are superior to common diseases, when developing innovative treatment methods, is a topic that will be discussed in Chapter 14.

Currently, drug development for the rare diseases is far exceeding anything seen in the common diseases. Since 1983, more than 350 drugs have been approved to treat rare diseases (7). In 2011, the U.S. Food and Drug Administration has designated over 2,300 medicines as orphan drugs (See Glossary item, Orphan drug). That same year, 460 drugs were in development to treat or prevent the rare diseases (7). Meanwhile, in Europe, 20% of the innovative products with marketing authorization were developed for a rare disease (1).

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases jules j berman


[1] Ayme S, Hivert V (eds.), "Report on rare disease research, its determinants in Europe and the way forward", INSERM, May 2011. Available from: http://asso.orpha.net/RDPlatform/upload/file/RDPlatform_final_report.pdf, viewed February 26, 2013.

[2] Pauling L, Itano HA, singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science 110: 543-548, 1949.

[3] Ingram VM. A specific chemical difference between globins of normal and sickle-cell anemia hemoglobins. Nature 178:792-794, 1956.

[4] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245:1066-1073, 1989.

[5] Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, et al. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther 19:979-90, 2008.

[6] Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci USA 110:E517-525, 2013.

[7] Orphan Drugs in Development for Rare Diseases; 2011 Report. America's Biopharmaceutical Research Companies. Available from http://www.phrma.org/sites/default/files/pdf/rarediseases2011.pdf, viewed July 14, 2013.