Download Treatments I

Treatment of genetic diseases
• what can be done?
Can be treated in many levels:
• Genetic consultation
• Treatment of symptoms
• Disease specific
treatment
• Gene therapy
1) Genetic consultation
• Information about the disease, its inheritance and genetic
risk of occurence in an understandable way
• Determination of genetic risk to be used in prevention
– Inheritable colon cancer
– Followup permits detection and removal of tumor in early phase
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Carrier testing (family planning)
Prenatal diagnostics (testing of unborn babies)
Disease cannot be deleted
Right to remain also ignorant
 knowledge can be burden in cases  disease cannot
not be affected
2) Treatment of symptoms
• Often the only way to
help affetcted
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Pain killers
Blood transfusions
Surgery
Physiotherapy
Etc
3) Disease specific treatment
• Inborn errors in metabolism
– Reduce the formation of toxic
metabolites
– Replacement of missing protein,
eg. enzyme
– Regulation of abnormally
functioning metabolic reaction
• Dietary changes or
pharmacologically
3) Disease specific treatment
A) Dietary change
• Phenylketouria – minimization of Phe
• Organic acidemias – minimization of Ile, Val, Met, Thr
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e.g. methylmalonyl-CoA mutase -works with vitamin B12 to
break down amino acids, certain lipids, and cholesterol
Abnormal buildup of organic acids  in the blood, urine and
tissues can be toxic and can cause serious health problems.
limited protein/high carbohydrate diet, vitamin supplementation,
carnitine
Maple syrup urine disease – minimization of Val, Leu, Ile
Defect of urea cycle- residual nitrogen
Galactosemia
Fructose intolerance
Lactose intolerance
Hypercholesterolemia
For life
3) Disease specific treatment
B) Alteration of enzymatic activity
• Induction and inhibition
• barbiturates
– Induction of liver enzymes, eg. in treatment of bilirubin
conjugations defects
• statins
– inhibition of the key enzyme of cholesterol synthesis
3) Disease specific treatment
C) Replacement therapy
• Defects in hormone synthesis
– Insulin, thyroxine, cortisol,
parathormone or analog
• Cofactor replacement
= defective enzyme activity
can be increased with a
cofactor or a precursor of the
vitamin
– Lack of biotidinase  biotinin
supplement
– EDVI  vitamin C supplement
• Lack of enzyme leads to
deficit in the product
– glucose - glycogenosis
• Enzyme replacement
= recombinant protein,
intravenously
– In 2 lysosomal diseases
– Glucocerebrosidase Gaucher disease
– Alfa-galactosidase– Fabry
disease
– Currently primary treatment
in these diseases
3) Disease specific treatment
D) Manipulation of
metabolites, use of
diversion
• Defects of urea cycle
– Sodium benzoate- removal of
ammonia (nitrogen)
• Familial hypercholesterolemia
– Cholestyramin binds bile acid 
prevents the absorption of
cholesterol
– Statins – inhibit the synthesis of
cholesterol
• Phenylketouria
– Phelnylalanine ammonialyase
(PAL) degrades Phe into
ammonium and trans-cinnamate
3) Disease specific treatment
E) Elimination of toxic
metabolites
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Secretion as a complex
Chelation
Plasmapheresis
Dialysis
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Penisillamin prevents accumulation of
Cu2+- Wilson disease
Nitisinone enzyme inhibitor is used to
inhibit the formation of toxic products
in - hereditary tyrosinemia type I
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- Competing inhibitor
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Lost in tyrosinemia
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expression with drugs
• Hydroxyurea stimulates
production of fetal Hb –
sickle cell aneamia
• Ataluren has been accepted
as a drug in treatment of
Duchenne muscle dystrophy
patients with premature
STOP codon  truncated
protein
– Drug increases the ability of
ribosome to bypass stop codon
and facilitates the translation of
full length dystrophin
Pediatric Research (2014) 75, 196–204
F) Alteration og gene
http://www.ptcbio.com/ataluren
3) Disease specific
treatment
4) Transplantation
• Liver and bone marrow transplantations - ” a pre-gene
therapy”
 transplantation of healthy tissue brings functional
genome into body
• Disadvantage is a lifetime use of immunosuppressant drugs
• Also heart, kidney, pancreas and liver transplants
• Liver transplantations in metabolic diseases
– Tyrosinemia, defects in in bile acid synthesis
• Bone marrow, umbilical cord blood cell and stem cell
transplantations
– Aim is to deliver an adequate amount of enzyme activity into tissues
most severely affected by intracellular accumulations
– Some lysosomal and peroxisomal diseases
– Stem cell treatments in blood cell cancers
Gene therapy
• Transfer of therapeutic gene into diseased
tissue/cell
• Aim is to have long lasting expression in target
tissue
• Approaches:
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Gene correction
Gene augmentation
Targeted killing of specific cell
Gene ablation
Gene therapy approaches
Targeted gene correction
• Aim to introduce a specific mutation in the gene of
interest – inherited diseases
• Targeting is based on homologous recombination
Gene therapy approaches
Gene augmentation
• Used to treat diseases with a loss of function mutation
 adds a functional gene back into the cell
• Transfered gene produces a functional product at a sufficient
level to maintain normal tissue function
• Successful if the disease has not resulted in unrecoverable
damage to body
Gene therapy approaches
Targeted killing of specific cells
• Suitable for diseases like cancer that can be treated by destroying certain groups of
cells
• Aim is to insert DNA into a diseased cell
– contains a “suicide” gene that produces a toxic product which kills the cell
– causes expression of a protein that marks the cells so that it is attacked by
immune system or drug
• Appropriate targeting of
inserted DNA is crucial to
avoid death of normal cells
Gene therapy approaches
Gene inhibition /ablation
• Suitable for treatment of infectious diseases, cancer and inherited
diseases caused by inappropriate gene activity
• Product of introduced gene is used
– Targeted inhibition of gene expression
– Interferes with the activity of a gene product
• Aim is to eliminate the activity of a gene that encourages the
growth of disease-related cells
In vivo gene
therapy
• Genetic material is transferred
directly into the body of the
patient
– More or less random
process
– small ability to control
– less manipulations
• Only available option for
tissues that cannot be grown in
vitro or grown cells can not be
transferred back
Ex vivo gene therapy
• The genetic material is first transferred into cells grown
in vitro
– Controlled process
– transferred cells are selected and expande
– more manipulations
• Cells are usually autologous; they are returned back to
the patient
When gene therapy treatment?
• There is no other treatment available
• Severe disease
• Success can lengthen the life
– Is lengthening of couple of months enough?
– Returns life back to normal
• Defect in one gene
• A small increase enzyme activity in
recessive diseases is often enough