Alpha Mannosidosis is an autosomal recessive disease where mutations in the MAN2B1 gene results in defective alpha-D-mannosidase activity resulting in accumulation of mannose-rich oligosaccharide chains within cells. This accumulation is responsible for many problems that affect individuals with this disease. The symptoms and severity of the disorder are highly variable. Symptoms may include distinctive facial features, skeletal abnormalities, hearing loss, intellectual disability, and dysfunction of the immune system.
Alpha-mannosidosis is best thought of as a continuum of disease that is generally broken down into three forms: a mild, slowly progressive form (type 1); a moderate form (type 2); and a severe, often rapidly progressive and potentially life-threatening form (type 3). The prevalence of this disease is estimated at about 1 in 500,000 people.
The recombinant enzyme drug Lamzede® (velmanase alfa, Chiese Farmaceutici) was approved for treatment of non-neurological symptoms of alpha mannosidosis by the European Medicines Agency in 2018.
There are two major disease phenotypes: the type 1 “classic” and type 2 “later-onset” subtypes. Both lead to renal failure, and/or cardiac disease, and early death. Type 1 males have little or no functional a-Gal A enzymatic activity and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels result in major disease symptoms in childhood or adolescence. Without treatment, the average life expectancy of affected males with the type 1 classic phenotype is about 40 years. The incidence of males with type 1 Fabry disease is about 1 in 40,000 males.
Males with the type 2 “later-onset” phenotype have some a-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not manifest the early manifestations of type 1 males. Instead, they typically develop renal and/or cardiac disease in the third to seventh decades of life. The incidence of type 2 later-onset males is at least 10 times more frequent than that of the type 1 males from the same region, ethnic group, or race.
The recombinant enzyme drug Fabrazyme® (agalsidase beta, Sanofi-Genzyme) was approved for treatment of Fabry disease by the European Medicines Agency in August 2001 and by the FDA in April 2003. The drug Replagal (agalsidase alfa, Takeda-Shire) was approved for clinical use by the European Medicines Agency in August 2001. PRX-102 (pegunigalsidase alfa, Protalix Biotherapeutics) is in phase 3 testing, while Moss-aGal (agalsidase alfa, Greenovation Biotech GmbH) is in phase 2 testing.
Gaucher’s disease is an autosomal recessive disease due to mutations occurring in the GBA gene that encodes the enzyme beta glucocerebrosidase, which breaks down the lipid glucocerebroside in lysosomes. Gaucher disease is diagnosed in three forms: type 1, also called non-neuronopathic Gaucher disease because the brain and spinal cord are usually not affected; type 2, which affects the nervous system and usually causes life-threatening medical problems beginning in infancy; and type 3, which also affects the nervous system but it tends to worsen more slowly than type 2. Signs and symptoms include hepatomegaly and splenomegaly, joint pain, neurological issues and osteoporosis.
Gaucher disease type 1 occurs much more frequently in Ashkenazi Jews and is the type of Gaucher most often diagnosed in North America and Europe. Here the prevalence is about 1 in 50,000 in these regions. Types 2 and 3 are more usually found in non-Western populations but are rarer, with a prevalence of about 1 in one million people.
A number of enzyme replacement drugs have been approved for Gaucher disease type 1, including Cerezyme® (imiglucerase alfa, Sanofi-Genzyme), approved for use in over 50 countries since 1994; Vpriv® (velaglucerase alfa, Takeda-Shire), approved by the FDA in February 2010; Elelyso® (taliglucerase, Pfizer) approved by the FDA in 2012 and in a number of other non-EU countries. Abcertin® (imiglucerase, Ibu Abxis), a biosimilar of Cerezyme, has been approved for market in South Korea, Mexico, Iran, and the Honduras.
The onset of disease typically occurs within the first two years of life when the child may exhibit coarse facial features, clouding of the cornea, enlarged liver and spleen, a large tongue, skeletal abnormalities, poor growth, joint stiffness, and a prominent forehead. Symptoms of MPS 1 can vary widely. In MPS 1H, children can additionally experience developmental delays, hydrocephalus, recurrent urinary and upper respiratory infections, noisy breathing and a persistent nasal discharge. They may develop back curvature and severe joint stiffness with clawlike hands. In the milder form of MPS I, known as Scheie syndrome, symptom onset occurs later and patients typically have normal intelligence, stature and life expectancy, but suffer from physical symptoms such as stiff joints, clouding of the cornea, and flow of blood from the aorta back into the left ventricle of the heart (aortic regurgitation). MPS type 1 is very rare, with a prevalence of less than 1 in 100,000.
There is a single enzyme replacement therapy for MPS 1, Aldurazyme® (laronidase, BioMarin Pharmaceutical Inc.), approved in the US and in the EU in 2003. An ERT designed to pass through the blood-brain barrier, AGT-181 (ArmaGen, Inc.) is in phase 2 testing.
There is a single enzyme replacement therapy for MPS 2, Elaprase® (idursulfase, Takeda-Shire), approved in the US in 2006 and in the EU in 2007. An ERT designed to pass through the blood-brain barrier, JR-141 (JCR Pharmaceuticals, Ltd.) is in phase 3 testing.
There is a single enzyme replacement therapy for MPS 4A, Vimzim® (elosulfase alfa, Biomarin Pharmaceutical Inc.), approved in the US in February 2014 and in the EU in April 2014.
The enzyme replacement therapy Naglazyme® (galsulfase, BioMarin Pharmaceutical Inc.) was approved for treatment of MPS 6 by the FDA in May 2005 and by the EMA in January 2006.
MPS 7, also called Sly disease, is an autosomal recessive disorder cause by mutations of the GUSB gene, resulting in deficient beta glucuronidase, the enzyme that breaks down β-D-glucuronic acid residues from heparan sulfate in the lysosome. The accumulation of these products results in dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, severe hypotonia and neurological disorders that ultimately lead to profound intellectual deficit and small stature in patients that survive. Many instances of the disease manifest pre-natally or shortly after birth, although there have been mild cases only diagnosed in adolescence or early adulthood. It is a very rare disease with a prevalence of less than 1 in one million people.
There is only one enzyme replacement therapy for this disease: Mepsevii® (vestronidase alfa, Ultragenyx Pharmaceuticals). The drug was approved for clinical use by the FDA in November 2017 and by the EMA in August of 2018.
The recombinant enzyme drug Brineura™ (cerliponase alfa, BioMarin Pharmaceutical Inc.) was approved for treatment of CLN2 disease by the FDA in April 2017 and by the European Medicines Agency in June 2017.
There are no approved enzyme replacement therapies for Niemann-Pick type B but Sanofi-Genzyme has a recombinant drug, olipudase alfa, in phase 3 studies.
There is an enzyme replacement therapy available for Pompe disease. Myozyme® (alglucosidase alfa, Sanofi Genzyme) was approved for use by the EMA in March 2006 and by the FDA in April 2006. In 2010, the FDA and EMA approved a larger-scale version of the drug, Lumizyme®.