Download - Therapeutic Enzymes
Presented by - R Hemamalini 2010CYZ8795 Group G1
2.
Market Scenario
Sources
Technologies for production
Enzyme Replacement Therapy
Enzyme treatment for special conditions
Introduction
Enzymes are biological catalysts, usually proteins that
accelerate chemical reaction rates by a million fold or more.
The hallmarks of enzyme action are specificity, and
efficiency. They are essential for cell and tissue viability.
Clinical consequences result in their absence or malfunction.
Therapeutic enzymes are those enzymes which can be safely
used in medicine to cure diseases and medical conditions
effectively and safely. Medication may involve only the
concerned enzyme or in combination with other therapies.
3.
High affinity
Specificity
Potent
Incentives
4.
Need encapsulation
Long-term dependency
High Purity
Immunogenic
5.
The use of animal enzymes instead of microbial enzymes,
although these would be costlier.
Modified by covalent attachment of polyethylene glycol, for
e.g in asparaginase
Entrapment of the enzyme within artificial liposomes,
synthetic microspheres and red blood cell ghosts.
Choose the sources carefully to avoid any unwanted
contamination by incompatible material and to enable
ready purification.
Use prophylactic enzymes as a short-term aid only.
6.
Enzymes in
medicine
EnzymeReplacement
TherapyProphylaxis
Treatingspecial
conditions
Extraction of
medically important compounds
DiagnosisDrug
manufacture
CancerWound healing
Lactose intolerance
Clotting Anti-clotting
7.
Deficient enzyme activity
Accumulation of key products or substrates ERT
Clinical symptoms
Alleviation of symptoms
8.
Adequate drugs for many of rare diseases and conditions have
not been developed – Orphan drugs
Passed in 1983 in the United States
Encourage pharmaceutical companies to develop treatments for
diseases affecting only small numbers of people (less than 200
000).
In Europe and Australia, there is comparable legislation that
provides similar protection and incentives
9.
Source:- Stefano Villa, Amelia Compagni and Michael R. Reich (2008) Orphan drug legislation: lessons for neglected tropical diseases, Int J Health Plann Mgmt,2008
10.
Adenosine deaminase - EC 3.5.4.4
Severe Combined Immunodeficiency (SCID)
Autosomal recessive, frequent infections result in early death.
Intracellular purine metabolites accumulate to toxic
concentrations within cell. T-cell and B-cell function absent
from birth
ADAGEN® (Pegademase Bovine) – Enzon Inc. Sigma-Tau
Pharmaceutical Inc. modified enzyme for ERT derived from
bovine intestine – injections
rh ADA developed by R&D systems, Minneapolis, but for
research only, Feb, 2011.
11.
Adenosine and deoxyadenosine accumulate
inhibit S-adenosyl homocysteine hydrolase
accumulation of SAH
failure of methylation reactions
(important for detoxification of adenosine and deoxyadenosine)
12.
Congenital sucrase-isomaltase deficiency (CSID)
An autosomal recessive disease of the small intestine first discovered
in 1960 by Weijers and colleagues.
Sucrase and maltase activity absent or minimal.
Sucrase replacement therapy with 100-fold more potent enzyme –
Sucrosidase - Sucraid
Liquid form, Saccharomyces cerevisiae-derived, oral solution
8,500 I.U per ml of sucrase
Orphan drug in 1998 by FDA
Sucrase – isomaltase EC 3.2.1.10(/48) 13.
14.
Deficiency of the above enzyme -> Phenylketonuria (PKU)
Genetic disease
Treatment from birth with a low phenylalanine diet.
Phenyl alanine ammonia lyase - EC 4.3.1.5 acts as a substitute
for the deficient enzyme.
PAL,converts phenylalanine to trans-cinnamic acid, a harmless
metabolite.
Sources: Plants, recombinant
Modified with PEG for stability
Phenylalanine monooxygenase (EC 1.14.16.1)
15.
16.
Gaucher’s
disease
Found by
Phillipe Gaucher
in 1882
Biochemical
basis for the
disease in 1965
by Brady et al..
Glucosyl
CH2-CH-CH-CH=CH-(CH2)12-CH3
O=C-CH2-CH2-CH2-(CH2)n-CH3
N OH
Ceramide
OH-CH2-CH-CH-CH=CH-(CH2)12-CH3
O=C-CH2-CH2-CH2-(CH2)n-CH3
N OH
Glucose Ceramide
Glucocerebrosidase - EC 3.2.1.45 Glucocerebrosidase - EC 3.2.1.45
Cerebrosidase /β-glucosidase
17.
The lack of the glucocerebrosidase, a β- glucoronidase
leads to accumulation of glucocerebroside.
Autosomal recessive disorder
Ceredase - ERT with β- glucoronidase extracted from
human placental tissues, from Genzyme
Cerezyme – recombinant human enzyme expressed in
chinese hamster ovary cells from Genzyme.
Annual cost of ERT: $80,000 for each patient annually.
Administered as injections.
19.
20.
DIGESTIVE SYSTEMIC
Amylase
Lipase
Protease
Lactase
Cellulase
Nattokinase
Serratio-
peptidase
Proteolytic
Source:- The Enzyme Revolution by Enzymedica
21.
Bilirubin oxidase
Heparinase
Sucrase-isomaltase
Ribonuclease T1
L-Asparaginase
Collagenase
Streptokinase
Serratiopeptidase
Uricase
Papain
Bromelain
Phenylalanine ammonia lyase
Nattokinase
Amylase
Glucocerebrosidase
DNase
Urokinase
Alpha Glucosidase
Hyaluronidase
UrokinaseTrypsin
Chymotrypsin
22.
Microbial production
Mammalian cell processes
Plant cultivation
Recombinant DNA technology
23.
Source:- Protein expression workflow by Sigma-Aldrich
The global market for medical enzymes was estimated at $6
billion in 2010.
The market is growing at a compound annual growth rate
(CAGR) of 3.9%, to reach $7.2 billion in 2015.
Therapeutic enzymes are the biggest segment in terms of
revenues generated- valued at $5.3 billion in 2010 and expected
to reach $6.3 billion in 2015, at a 3.6% compound annual growth
rate (CAGR) .
Enzymes used in molecular research will experience the fastest
compound annual growth rate (CAGR), 6.2%, over the study
period. This sector was worth $546 million in 2010 and should
reach nearly $739 million by 2015. Source: BCC Research on Medical Enzymes: Technology and Global Markets
24.
Total enzyme consumption figures of India are
comparatively low: A major difference is noticed in the
enzyme consumption pattern, compared to world figures,
e.g. the use of enzyme in detergents is much smaller.
Special efforts are needed to formulate favourable
government policies to promote academic-industry
interaction.
Some companies like: Advanced Enzymes, Biocon, Bharat
Pharma are producing therapeutic enzymes.
Source:
TIFAC Report on Bioenzymes: Production technology
Website of Advanced Enzymes, Biocon and Bharat Pharma
25.
1. BCC Research on Medical Enzymes: Technology and Global Markets
2. Cerezyme Imiglucerase for Injection -
http://www.cerezyme.com/~/media/Files/CerezymeUS/pdf/cerezyme_pi.pdf
3. Christineh N. Sarkissian, Zhongqi Shao, Franc Oise Blain, Rosalie Peevers, Bongsheng Su,
Robert Heft, Thomas M. S. Chang and Charles R. Scriver, A different approach to treatment
of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia
lyase, Proc. Natl. Acad. Sci. USA Vol. 96, pp. 2339–2344, March 1999
4. D. R. HeadonAnd G. Walsh, The industrial production of enzymes, Biotech. Adv. Vol. 12, pp.
635--646,1994
5. David J. Saul, Moreland D. Gibbs and Peter L.Bergquist, Biocatalysis: Industrial Enzymes and
the exploitation of micro-organisms, New Zealand Institute of Chemistry
6. Enzymes: EC Nomenclature – 4th level Complete List of all Enzymes,
http://www.biologie.uni-hamburg.de/b-online/e18_1/ec4.htm
7. Jennifer Hammer, Stan Bynum, Therapeutic Use of Enzymes for Vollara
8. Michael Vellard, The enzyme as drug: application of enzymes as pharmaceuticals, Current
Opinion in Biotechnology 2003, 14:1–7
9. Michel Duval, Stefan Suciu, Alina Ferster, Xavier Rialland, Brigitte Nelken, Patrick Lutz, Yves
Benoit, Alain Robert, Anne-Marie Manel, Etienne Vilmer, Jacques Otten and Noël Philippe,
Comparison of Escherichia coli-asparaginase withErwinia-asparaginase in the treatment of
childhood lymphoid malignancies: results of a randomized European Organisation for
Research and Treatment of Cancer--Children's Leukemia Group phase 3 trial, Blood, 15
April 2002 Volume 99, Number 8
10. Protein expression workflow by Sigma-Aldrich
11. Rodney J.Y Ho, Milo Gibaldi (2003) in Biotechnology and Biopharmaceuticals, Wiley-Liss, NJ,
pp. 245-269
12. Stefano Villa, Amelia Compagni and Michael R. Reich (2008) Orphan drug legislation:
lessons for neglected tropical diseases, Int J Health Plann Mgmt,2008
13. Syndey Sandberg, Special Report: A nutraceutical approach to enhancing memory, Enzyme
News
14. The Enzyme Revolution by Enzymedica
15. Walsh, G (2003) in Biopharmaceuticals Biochemistry and Biotechnology, Wiley, West
Sussex, 2nd Ed., pp. 351-402
Dr. Ravi Krishnan Elangovan for inspiring me to take
up this topic
Prof. S.K. Khare for his support and guidance
My colleagues and friends for their help and critically
reviewing the content
My batchmates for helping me use their resources
Family for their patience and understanding