Gene-Encoded Enzyme Replacement Therapy for Lysosomal Storage Diseases

Enzyme replacement therapy (ERT) is used to compensate deficiencies of production of specific enzymes within the patient’s body—usually resulting from specific genetic defects—by delivering the missing protein on a periodic basis.

Enzyme replacement therapy is the standard therapy for a number of inherited diseases but is mainly used in treating lysosomal storage diseases. Lysosomes are cellular organelles responsible for the metabolism of many different macromolecules and proteins within the cell. The lysosomes utilize enzymes to break down these macromolecules, which are then recycled or disposed of. If genetic mutations prevent the production of certain enzymes used in the lysosomes, this often leads to a buildup of the substrate within the body. The accumulation of substrate can result in a variety of symptoms, many of which are severe and can affect the skeleton, brain, skin, heart, and the central nervous system. Increasing the concentration of missing enzyme in the blood provides cells the ability to correctly process these substrates. There are more than 50 lysosomal storage diseases, each of which is considered to be a rare/orphan disease with a prevalence of less than 1 out of 50,000 people. Lysosomal storage diseases for which enzyme replacement therapy is already approved or in late clinical development include:

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.

Fabry disease is an X-linked disorder from mutations in the GLA gene leading to deficient activity of the enzyme alpha-galactosidase A (a-Gal A). A-Gal A breaks down specific sugar-lipid molecules such as globotriaosylceramide (GL-3 or Gb3) and lyso-GL-3/Gb3. The enzyme deficiency causes a continuous buildup of GL-3/Gb3 and related glycolipids in the body’s cells, resulting in cell abnormalities and organ dysfunction that particularly affect the heart and kidneys.

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 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 Honduras.

A family of diseases called mucopolysaccharidoses affect enzymes that break down complex carbohydrates called mucopolysaccharides in the lysosome. MPS 1 arises from mutations in the gene IDUA and result in deficiencies of the enzyme alpha L-iduronidase, which breaks down unsulfated alpha-L-iduronic acid. This is an autosomal recessive disease with a continuum of symptoms. The most severe form of MPS 1 is often called Hurler syndrome (or MPS 1H). A milder form of MPS 1 is called Scheie syndrome (or MPS 1S), and the name Hurler-Scheie (MPS 1H/S) is sometimes applied to an intermediate form that does not fit clearly in either the milder or more severe category.

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.

MPS 2, also called Hunter syndrome, is an autosomal recessive disease resulting from mutations in the IDS gene leading to deficiencies of the enzyme iduronate-2-sulfatase. Patients with MPS 2 may experience a plethora of symptoms although the more severe cases are characterized by stunted growth, coarse facial features, stiff joints, and intellectual disability. MPS 2 affects mainly boys, and symptoms often begin around 2-4 years of age. The severe form often results in progressive cognitive impairment and limits the lifespan to about 12-15 years. In milder forms, the condition may go undiagnosed for many years as it does not result in intellectual impairment or regression. Other symptoms include hearing loss, joint stiffness, and thickening of heart valves. MPS 2 has a prevalence of less than 1 in 100,000 people.

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.

MPS 4A, also referred to as Morquio syndrome, is an autosomal recessive disease resulting from mutations in the GALNS gene leading to deficiencies of the enzyme iduronate-2-sulfatase. Onset of symptoms typically occurs in childhood. Affected individuals develop various skeletal abnormalities, including short stature, knock knees, and abnormalities of the ribs, chest, spine, hips, and wrists. People with MPS IV often have loose, very flexible joints but some may experience restricted movement in certain joints. A characteristic feature of this condition is underdevelopment of a peg-like bone in the neck called the odontoid process, which can lead to misalignment of the cervical vertebrae and compress and damage the spinal cord, resulting in paralysis or death. Severely affected individuals may survive only until late childhood or adolescence, while those with milder forms of the disorder usually live into adulthood, although their life expectancy may be reduced. MPS 2 has a prevalence of less than 1 in 250,000 people.

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.

MPS type 6, also known as Maroteaux-Lamy Disease, is an autosomal recessive disease arising from a mutation in the ARSB gene, leading to deficiencies in the enzyme arylsulfatase B, which allows the accumulation of dermatan sulfate in lysosomes. People with this disorder show a spectrum of symptoms from slowly to rapidly progressing forms. The disease affects skeletal growth resulting in short stature, dysostosis multiplex, and degenerative joint disease. It can also result in cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. While not specifically affecting the central nervous system, neurological complications result from spinal abnormalities. MPS 6 is relatively rare, with a prevalence of only about 1 in one million people.

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 caused 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 prenatally 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.

NCL2 is one of a family of 14 lysosomal storage diseases referred to collectively as Batten disease, and is the result of an autosomal recessive genetic mutation in the NCL2 (TPP1) gene resulting in deficiency of the enzyme tripeptidyl peptidase 1. This disease generally develops between ages two and four years, and affected children may experience speech delays, seizures that do not respond to medications, loss of muscle coordination, muscle twitches, loss of vision, developmental delays, and intellectual disabilities. The course of NCL2 is progressive. Its prevalence is less than 1 in 5 million.

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.

This autosomal recessive disease, like Gaucher disease, is prominent in Ashkenazi Jews. Here mutations in the SMPD1 gene cause deficiencies in acid sphingomyelinase. Signs and symptoms typically develop in the pre-teen years and may include hepatosplenomegaly, short stature, problems with lung function including frequent lung infections, and a low number of platelets in the blood. It has a prevalence of about 1 in 500,000 people, although in the Ashkenazi Jewish population it is about 1 in 40,000.

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.

Pompe disease is an autosomal recessive disease due to mutations in the GAA that leads to deficient acid maltase (acid ⍺-1,4-glucosidase) enzyme, resultant in the accumulation of glycogen in certain organs and tissues, especially muscles, which impairs their ability to function normally. Three types of Pompe disease have been described which differ in severity and the age at which they appear. The classic form of infantile-onset Pompe disease begins within a few months of birth, and children typically experience muscle weakness, poor muscle tone, an enlarged liver, and heart defects. Affected infants may also fail to gain weight or grow normally and may have breathing problems. Untreated infantile-onset disease leads to death from heart failure in the first year of life. The second form, non-classic infantile-onset Pompe disease, usually appears by age 1 and is characterized by delayed motor skills and progressive muscle weakness. Children may develop enlarged hearts, but unlike in classic infantile-onset, do not experience heart failure. Nevertheless, affected infants develop serious breathing problems and most only live into early childhood. The milder late-onset type of Pompe disease may not become apparent until later in childhood, adolescence, or even adulthood and is experienced as progressive muscle weakness, especially in the legs and the trunk, including the muscles that control breathing. As the disorder progresses, breathing problems can lead to respiratory failure. Pompe disease is a more common type of lysosomal storage disease with a frequency in the US of about 1 in 58,000 people. About one-third of patients have an infantile onset form of the disease.

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®.

ERT is used to minimize symptoms and prevent permanent damage to the body from substrate buildup

Typically, recombinantly produced enzymes—either replicating the natural protein or modified versions that can function similarly—are provided to the patient via periodic intravenous injection. ERT administration typically requires one to two hours and is repeated multiple times per month. Infusions are usually administered at infusion centers but under certain conditions can be administered at home by a nurse. The development of these complex therapies for markets of dozens, hundreds, or a few thousand people has resulted in pricing that typically ranges between $150,000 to $300,000 per patient per year.

Lysosomal Storage Disease Estimated Diagnosed Population  Current ERT Typical Dose/Frequency  Average Yearly Cost
Alpha Mannosidosis <5,000

Lamzede (alpha mannosidase)

1 mg/kg every week $400,000
Fabry Disease 15,000 Fabrazyme® (agalsidase beta)
Replagal (agalsidase alpha)
1 mg/kg every 2 weeks $220,000
Goucher Disease (Types 1 and 3) 10,000 Abstertin® (imiglucerase)
Cerezyme® (imiglucerase)
Elelyso® (taliglucerase)
Vpriv® (velaglucerase alfa)
1.5 mg/kg every 2 weeks $100,000 to $500,000
Lysosomal Acid Lipase Deficiency 15,000 Kanuma® (sebelipase alfa) 1 mg/kg every 2 weeks $250,000 to $500,000
Mucopolysaccharidosis Type 1 <5,000 Aldurazyme® (laronidase) 0.58 mg/kg every  weeks $200,000
Mucopolysaccharidosis Type 2 <1,000 Elaprase® (idursulface) 0.5 mg/kg every  weeks $375,000
Mucopolysaccharidosis Type 4A <500 Vimizim® (elosulfase alfa) 2 mg/kg every  weeks $365,000
Mucopolysaccharidosis Type 6 <500 Naglazyme (galsulfase) 1 mg/kg every  weeks $350,000
Mucopolysaccharidosis Type 7 <500 Mepsivi (vestronidase alfa) 4 mg/kg every 2  weeks $375,000
Neurol Ceroid Lipofuscinosis Type 2 <1,000 Brinuera® (cerliponase alfa) 300 mg/kg every 2 weeks $700,000
Niemann-Pick Type B <5,000 Olipudase alfa (in phase 3) 3 mg/kg every 2 weeks To be determined
Pompe Disease 10,000 Myozyme® (aglucosidase alfa) 20 mg/kg every  2 weeks $300,000

SmartPharm is focused on replacing the current administration of recombinant proteins with the approach of introducing the gene into the body that can make the protein needed over a long period of time. Unlike viral vectored therapies in development for ERT, SmartPharm’s non-viral DNA platform is minimally immunogenic and can be re-dosed as needed. We are working on approaches that would also eliminate the need for intravenous administration, making therapeutic treatment simpler for patients.

Successful gene-encoded therapeutics would prolong the period between treatment and could eliminate the infrastructure of infusion now required to deliver these proteins, thus freeing these patients from two of the significant burdens related to current ERT administration.