LYSOSOMAL STORAGE DISORDERS (LSD’s)

Lysosomal storage diseases (LSDs) are about 50 rare inherited metabolic disorders that result from defects in lysosomal function. They are characterized by an abnormal build-up of various toxic materials in the body’s cells due to enzyme deficiencies. New lysosomal storage disorders continue to be identified. While clinical trials are in progress on possible treatments for some of these diseases, there is currently no approved treatment for many lysosomal storage diseases.

Our mission is to improve people’s lives with rare diseases, and we are dedicating our efforts to 3 different Lysosomal Storage Disorders: Alpha mannosidosis, Nephropathic cystinosis, and Fabry disease.

Alpha Mannosidosis

The disease

Alpha Mannosidosis is a rare genetic disease caused by the impaired function of the lysosomal enzyme alpha-mannosidase. Due to this deficiency, oligosaccharides are only partially broken down. Over time, they build up in the body, causing increasing damage to cells and leading to medical problems in multiple body systems.

Alpha mannosidosis is a heterogeneous disease, presenting with a wide range of symptoms: the most frequent are recurrent chest infections and problems with hearing loss, distinctive facial features, cognitive impairment, and progressive muscular weakness. Lack of voluntary coordination of muscle movements and skeletal and joints abnormalities could occur. In adulthood, few patients manage to be completely independent socially, needing help with many activities, and possibly requiring a wheelchair.

High levels of oligosaccharides in urine are suggestive of alpha mannosidosis. Testing of the Mannosidase enzyme residual activity and genetic analysis is used to confirm the diagnosis.

Alpha mannosidosis is a rare disease, affecting approximately one in every million babies born worldwide.

If you want to discover more about alpha mannosidosis, please visit: www.alphamannosidosis.com

How is alpha mannosidosis treated?

The supportive treatments aim at controlling symptoms, and they involve several medical specialties.

Hematopoietic stem cell transplant (HSCT) can be a treatment option for some patients; however, the risk-benefit profile is more favorable in younger patients. Ensuring an early diagnosis is critical for this to be a real option for patients.

Nephropathic cystinosis

The disease

Nephropathic cystinosis is the most common and severe form of cystinosis. It is a metabolic disease characterized by an accumulation of the amino acid cystine within lysosomes in the cells, leading to widespread damage to organs and tissues.

Nephropathic cystinosis usually presents in early infancy as Fanconi syndrome, a serious disorder of the kidneys’ proximal tubules involving excessive excretion of nutrients and minerals such as glucose, amino acids, phosphates, potassium, and sodium. Neuropathic cystinosis can lead to excessive urination, resulting in acute dehydration. The loss of nutrients impairs growth and may result in soft, bowed bones. Untreated children will experience complete kidney failure by about the age of 10. However, nephropathic cystinosis is not only a renal disorder but a multisystemic disease that could lead to ocular and neurologic impairment, muscle deterioration, diabetes, thyroid and nervous system problems, and infertility in affected men.

Transmission is autosomal recessive: two altered copies of the gene from both parents are needed to manifest the disease. It is an ultra-rare disease, with an estimated incidence of around 1/100,000- 1/200,000 live births.

How is nephropathic cystinosis treated?

The primary treatment is cystine-depletion therapy (the pharmacological lowering of the cystine content in the lysosomes) through cysteamine that, when initiated early, can slow or even stop the progression to renal failure and the development of extra-renal manifestations.

In addition to cystine-depletion therapy, electrolytes and vitamin supplements are administered. Hormones and specific treatments are administered to support growth and to limit hypothyroidism, diabetes, and hypogonadism. Renal transplantation is the treatment of choice for end-stage renal disease in cystinosis.

Fabry disease

The disease

Fabry disease is a progressive, inherited, multisystemic lysosomal storage disease. It is characterized by sphingolipids’ accumulation due to the inherited deficiency of the enzyme alpha-galactosidase A.

Fabry disease is caused by mutations in the GLA gene, encoding the alpha-galactosidase A enzyme. This gene is located on chromosome X; therefore, males are affected while heterozygous females are carriers but may show a wide range of clinical manifestations.

The clinical picture covers a wide spectrum ranging from mild cases in heterozygous females to severe cases in classically affected hemizygous males with no residual alpha-galactosidase A activity. It is characterized by specific neurological, cutaneous, renal, cardiovascular, cochleovestibular, and cerebrovascular manifestations.

Incidence is reported to be 1 in 80,000 live births, but this figure may underestimate disease prevalence.

How is Fabry disease treated?

Nowadays, enzyme replacement therapy (ERT) is considered the standard treatment for Fabry disease. The recombinant alpha-galactosidase A enzyme is administered with intravenous injections. The earlier the treatment is initiated, the better are the treatment results.

Conventional management consists of pain relief with analgesic drugs, nephroprotection, and other symptomatic treatments. Some patients require dialysis and kidney transplant.

In October 2017, Chiesi announced an Ex-US license and collaboration agreement with Protalix BioTherapeutics, Inc. for the development and commercialization of PRX-102 (pegunigalsidase alfa), the Company’s chemically modified version of the recombinant alpha-Galactosidase-A protein for the treatment of Fabry disease. In July 2018, Protalix and Chiesi entered into an exclusive U.S. license and supply agreement, which grants to Chiesi the United States rights for the development and commercialization of PRX-102.