Orphan diseases are rare and often life-threatening diseases that typically do not have effective treatment options. Patients and families hope for treatment to over 6,000 orphan diseases. Targeted gene alteration without gene therapy offers a rational approach to developing life-changing treatments. The need for effective treatments to theses diseases is real and urgent.

OrphageniX has selected the following initial clinical targets:

Sickle Cell Disease

Sickle Cell Disease is a global health problem, afflicting all ages; 72,000 Americans and 1 in 500 African-Americans have the disease, 50% of those affected are children. The disease is an inherited blood disorder caused by a single point mutation in the hemoglobin gene (ß-globin). The clinical condition results from a homozygote sickle cell allele ß^S, where an A-to-T point mutation within the sixth codon of the ß-globin coding region changes the glutamic acid residue to a valine. The mutation causes red blood cells to become rigid and sickle-shaped, which can lead to lung tissue damage, pain episodes, stroke and damage to most organs including the spleen, kidneys and liver. Symptoms can range from mild to severe, and there is currently no cure available.

Additional information on Spinal Muscular Atrophy can be found at: http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_WhatIs.html

Spinal Muscular Atrophy

SMA types I, II, and III occur in childhood and has an incidence of approximately 4 per 100,000 people. SMA is the number one lethal genetic disease of children under two years of age; 50% of those diagnosed with SMA at birth die before age two. It is caused by a mutation in the survival motor neuron (SMN1) gene and affects the voluntary movement nerves in the anterior horn of the spinal cord. SMA leads to progressive muscle degeneration, weakness, and eventually death. SMA comprises a group of diseases, all of them severe. At least 23 different mutations have been identified to cause SMA, but correcting just one mutation in the nearly identical SMN2 gene will provide a functional copy of the necessary SMN1 gene. The most severe form, SMA I, usually kills infants before ages 2-3, while type II and III patients usually die in childhood or early adulthood. There is currently no cure available for the disease.

Additional information on Spinal Muscular Atrophy can be found at: http://www.ninds.nih.gov/disorders/sma/sma.htm

Alpha-¹ Antitrypsin Deficiency

Between 70,000 and 100,000 individuals suffer from alpha-¹ antitrypsin deficiency (AATD) in the United States. AATD is a liver disease caused by a single point mutation in the AAT gene, which causes early onset emphysema, COPD, asthma, and cirrhosis; all of which can lower life expectancy if developed. The mutation blocks the secretion of AAT, AT from the liver and accumulation of AAT protein causes destructive effects in the liver. At least 100 normal or deficiency alleles of the AAT gene have been described, but two most common deficiency alleles exist, PiS and PiZ, both of which involve single base-pair substitutions in either exon III (substitution of T for A) or exon V (substitution of A for G). The first symptoms of the disease usually occur between ages 20 and 50 but are accelerated in cigarette smokers. Protein replacement therapy is being investigated but it is not clear how effective this is. The only cure for the disease is liver transplantation .

Additional information on Alpha-¹ Antitrypsin Deficiency can be found at: http://ghr.nlm.nih.gov/condition=alpha1antitrypsindeficiency

Additional Orphan Disease Target Candidates

Achondroplasia – the most common genetic form of short-limbed dwarfism. Achondroplasia is a result of a mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes abnormality in cartilage formation.

Gaucher’s Disease – a lysosomal storage disease affecting the liver and spleen. The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase. This mutation causes cells to be unable to eliminate glococerbroside, which accumulates in fibrils.

Hereditary Hemochromatosis – an iron storage disorder leading to multi-organ failure. One of the most common cause of hereditary haemochromatosis is a single point mutation in the hemochromatosis (HFE) gene where the cystine residue at position 282 is changed into a tyrosine residue.

Pompe's Disease – a lysosomal storage disease affecting the brain and heart. This disease is caused by a mutation in the glucoside alpha acid (GAA) gene, which is needed to break down glycogen.

Retinitis Pigmentosa – a group of inherited vision disorders causing degeneration of the retina. There are multiple genes that, when mutated, can cause the Retinitis Pigmentosa phenotype. Most of those mutations are missense mutations.

Stargardt’s Disease – the most common genetic form of juvenile macular degeneration. Mutations in the ABCA4 gene cause the production of a dysfunctional protein that cannot perform energy transport to and from photoreceptor cells in the retina. The photoreceptor cells then degenerate, causing vision loss.