46
2.1
Introduction
Therapeutic usage of enzymes was in practice long ago with the application of
crude preparations of enzymes as digestive aids for gastrointestinal diseases. The
therapeutic potential of enzymes was first described when effective treatment of
anthrax by crude secretions from Bacillus pyocyaneus was performed, suggesting
that enzymes are responsible for the action. Now enzymes find clinical applications
as cardiovascular agents, oncolytics, digestive aids, in the replacement therapy of
lysosomal storage disorders, wound debridement therapeutics and so on. With the
progression of enzymology in the late nineteenth century, therapeutic applications
of newly discovered enzymes were explored apart from their use as digestive aids.
Investigations on digestive enzyme trypsin resulted in its application in the treatment of diphtheria by the removal of fibrous membrane formed in the throat during
the infection. Anti-cancer activity of trypsin was reported by John Beard, who proposed that defence against cancer was represented by pancreatic enzymes which are
proteolytic in nature (Beard 1906). Attracted by Beard’s hypothesis, physicians
started injecting pancreatic enzymes for cancer treatment, but after his death, attention towards Beard’s cancer treatment dropped. Trypsin was commercially available for oral administration as well as injection marketed by leading manufactures
like Merck and Fairchild in the 1900s. In the 1920s Edward Howell observed that
enzyme-rich raw food was reducing digestive load and promoting health. In 1932
he founded the National Enzyme Company for the production of enzyme supplements, substituting the enzymes lost while cooking and thus improving digestion.
The main advantage of an enzyme drug is its specificity. Enzymes specifically
bind to target molecules, which make enzymes stand out from any other class of
drugs. Also enzymes perform catalysis of multiple molecules. Therapeutic use of an
enzyme against genetic diseases was initiated by De Duve for the treatment of lysosomal storage diseases (De Duve 1966). This opened the way for enzyme replacement therapy. In 1983 the Orphan Drug Act was passed in the USA to support the
development of therapeutics against rare diseases for which suitable drug and treatment measures were not developed. For diseases such as lysosomal storage disorders due to lack of enzymes, this was a boon. Since then many of the therapeutic
enzymes for the treatment of rare diseases have been developed.
The first genetically engineered drug to be approved was a recombinant tissue
plasminogen activator alteplase (Activase
®
) in 1989. Later many cardiovascular
enzymes were developed and approved by the USFDA. Adagen, used for the treatment of severe combined immunodeficiency (SCID), was the first therapeutic
enzyme application against genetic disease. Enzyme therapies contribute a prominent share in clinical practice these days.
There are some limitations to therapeutic applications of enzymes as well.
Primarily the large size makes it difficult to get distributed. This can be evaded by
enzyme targeting. Some of the targeting methodologies include covalent linkage
with specific molecules such as mannose-6-phosphate or development of an
enzyme-monoclonal antibody complex. Secondly, the enzyme upon intravenous
infusion was generally treated as a foreign substance by the body. This could elicit
S.S. Kumar and S. Abdulhameed
2.1
Introduction
Therapeutic usage of enzymes was in practice long ago with the application of
crude preparations of enzymes as digestive aids for gastrointestinal diseases. The
therapeutic potential of enzymes was first described when effective treatment of
anthrax by crude secretions from Bacillus pyocyaneus was performed, suggesting
that enzymes are responsible for the action. Now enzymes find clinical applications
as cardiovascular agents, oncolytics, digestive aids, in the replacement therapy of
lysosomal storage disorders, wound debridement therapeutics and so on. With the
progression of enzymology in the late nineteenth century, therapeutic applications
of newly discovered enzymes were explored apart from their use as digestive aids.
Investigations on digestive enzyme trypsin resulted in its application in the treatment of diphtheria by the removal of fibrous membrane formed in the throat during
the infection. Anti-cancer activity of trypsin was reported by John Beard, who proposed that defence against cancer was represented by pancreatic enzymes which are
proteolytic in nature (Beard 1906). Attracted by Beard’s hypothesis, physicians
started injecting pancreatic enzymes for cancer treatment, but after his death, attention towards Beard’s cancer treatment dropped. Trypsin was commercially available for oral administration as well as injection marketed by leading manufactures
like Merck and Fairchild in the 1900s. In the 1920s Edward Howell observed that
enzyme-rich raw food was reducing digestive load and promoting health. In 1932
he founded the National Enzyme Company for the production of enzyme supplements, substituting the enzymes lost while cooking and thus improving digestion.
The main advantage of an enzyme drug is its specificity. Enzymes specifically
bind to target molecules, which make enzymes stand out from any other class of
drugs. Also enzymes perform catalysis of multiple molecules. Therapeutic use of an
enzyme against genetic diseases was initiated by De Duve for the treatment of lysosomal storage diseases (De Duve 1966). This opened the way for enzyme replacement therapy. In 1983 the Orphan Drug Act was passed in the USA to support the
development of therapeutics against rare diseases for which suitable drug and treatment measures were not developed. For diseases such as lysosomal storage disorders due to lack of enzymes, this was a boon. Since then many of the therapeutic
enzymes for the treatment of rare diseases have been developed.
The first genetically engineered drug to be approved was a recombinant tissue
plasminogen activator alteplase (Activase
®
) in 1989. Later many cardiovascular
enzymes were developed and approved by the USFDA. Adagen, used for the treatment of severe combined immunodeficiency (SCID), was the first therapeutic
enzyme application against genetic disease. Enzyme therapies contribute a prominent share in clinical practice these days.
There are some limitations to therapeutic applications of enzymes as well.
Primarily the large size makes it difficult to get distributed. This can be evaded by
enzyme targeting. Some of the targeting methodologies include covalent linkage
with specific molecules such as mannose-6-phosphate or development of an
enzyme-monoclonal antibody complex. Secondly, the enzyme upon intravenous
infusion was generally treated as a foreign substance by the body. This could elicit
S.S. Kumar and S. Abdulhameed