Technological Landscapes: The Healing Power of Enzyme Replacement Therapy

It takes a global pharmaceutical company with extensive resources to produce drugs that can alleviate suffering due to unheralded diseases. This is the challenge that Shire plc has chosen for their mission and the Lexington-based Shire’s Human Genetic Therapies (HGT) business unit exemplifies this effort. The business unit focuses on the research, development and marketing of “novel products and services that profoundly enhance the quality of life of patients suffering from rare diseases”.

Rare diseases afflict thousands rather than millions of people world-wide. In the United States, medication to alleviate such diseases are often termed orphan drugs and are subject to the Orphan Drug Act of 1983. This Act is designed to encourage research and development in rare diseases where the chance for financial return represents high risk. Modified clinical testing revisions are established for drug approval and include smaller test groups, tax incentives and clinical research subsidies. The price to administer a rare drug procedure is on the order of $200,000.

The rare diseases that Shire’s HGT unit designs and markets drugs for include Hunter syndrome, Fabry disease and Gaucher disease. The drugs created to alleviate the diseases are Elaprase, Replagal and VPRIV, respectively.

All three debilitating diseases have a common factor: they are a result of metabolic malfunctions within the smallest unit of life, the cell.

The human cell consists of essentially two parts: First, the DNA that controls heredity that is tightly wound in the form of chromosomes within the cell’s nucleus. Second, there is a cooperative set of components (organelles) that receive information from the DNA through its genes and in turn control the cell’s life. (Re: Teresa Audesirk and Gerald Audesirk, Biology, 4th Ed., Prentice Hall, N.J., 1996, Ch. 5)

One of the organelles is termed the lysosome. The lysosome receives digestive enzymes (protein-catalysts) from other organelles and then uses the enzymes to provide the cell’s digestive system. Specifically, the lysosomes provide two functions: they collect food particles and convert them into products needed to nourish the cell and they digest destructive organelles and recycle them for use by the cell.

When the enzymes in the lysosome are unable to effectively break-down the food material there is an accumulation of disruptive debris that builds in the cells throughout the body and essentially shuts-down numerous bodily functions. The result is severe, progressive and life-ending diseases. This class of diseases is known as Lysosomal Storage Disease (LSD).

LSDs include at least fifty rare, inherited metabolic disorders that can be traced to Lysosomal dysfunction. The diseases primarily afflict children but can last into adulthood. Symptoms include early death, developmental-delay, seizures, dementia, deafness, blindness, enlarged livers, cardiac problems and abnormal bone growth.

However, once the digestive enzyme can be identified DNA replication can be used to obtain properly functioning enzymes that can be infused into the patient to replace the defective enzymes.

This is the extraordinary procedure developed by the Shire HGT group called Enzyme Replacement Therapy (ERT). Each of the drugs mentioned above are designed to replace specific defective digestive enzymes.

The HGT group uses a proprietary replication process based on human cell lines to manufacture the LSD drug line. The distribution of such drugs extends globally to at least forty countries, including the United States, the European Union member states and Israel.

Impressive results were recently announced by Shire in regard to VPRIV, an ERT drug designed to alleviate Gaucher-related bone disease. Bone abnormalities are common for Type I Gaucher disease - the most prevalent type of Gaucher affliction. Type I Gaucher occurs in one in fifty-thousand live births world-wide. For Jews who originated in Eastern Europe (Ashkenazi) the birth incidence is one in four-hundred and fifty. Critically, VPRIV contains a replacement digestive enzyme that has the exact human amino acid sequence as that found in the naturally-occurring human enzyme thus minimizing side-effects.

The clinical trial was a head-to-head comparative analysis between Shire and a competitor and only patients treated with VPRIV experienced statistically-significant improvement in lumber-spine bone-mineral-density at the nine month check point. Professor Ari Zimran, Shaare Zedek Medical Center, Hebrew University and Hadassah Medical School, Jerusalem, Israel stated that, “These study results show that VPRIV is effective in treating selected markers of Gaucher-related bone disease, allowing patients to achieve an important therapeutic goal quickly.”

The Shire biopharmaceutical pipeline is filled not only with human-genetic-therapy drugs to treat ERT but with medications designed to alleviate attention-deficit-hyperactivity-disorder (ADHD), gastrointestinal (GI)disorders, and medicine to aid in the regeneration of active living cells.

Shire’s desire to allow children to walk where there had been no hope before is exemplified in their motto, “To be as brave as the people we help”.