Treatment of Genetic Disease Flashcards
Why is it difficult to cure genetic disease
Because every single cell in your body is fucked
Trisomy Treatment
Supportive care and better cardiac surgery has increased mean survival from 25 to 49
Multiple Endocrine Neoplasia Treatment
Genetic testing for autosomal dominant mutations IDs presymptomatic carrier –> take out thyroid (prevent thyroid carcinoma)
Multiple Endocrine Neoplasia - inheritance pattern?
how does genetic relate?
Autosomal dominant
Use genetic testing to manage disease (remove thyroid if have mutation)
Metabolic diseases
Usual inheritance pattern
autosomal recessive
Metabolic diseases (e.g. PKU) How do we target?
Newborn screening
Diet modification - low phenylalanine diet
How can we target alpha-1 AT?
Protein replacement therapy
Recombinant AT1 therapy
How can we target Fabry disease?
Alpha galactosidase
Protein replacement therapy
My patient has G6PD deficiency, what would I tell him to avoid?
Antimalarial drugs
My patient has Acute intermittent porphyria, what would I tell him to avoid?
Barbiturates
My patient has PKU, what would I tell them to avoid?
Phenylalanine
My patient has Galactosemia, what would I tell them to avoid?
Galactose
My patient has Congenital hypothyroidism, what would I give them
Thyroxine
My patient has biotinidase deficiency, what woudl I give them
Biotin
My patient has Urea cycle deficieny, what would I give them
Sodium benzoate
My patient is heterozygous for hypercholesterolemia
what diversion would I give them
what inhibitor would I give them?
oral resin diversion
statin drug inhibition
My patient is homozygous for hypercholesterolemia, what depletor would I give them
LDL apheresis
Target at level of mutant protein
What would I give homocystinuria patient?
pyridoxine
50% respond
cofactor replacement
What would I give my patient with hemophilia?
factor VIII
extracellular replacement
What would I give my patient with alpha-1 AD?
Alpha-1 Antitrypsin
extracellular replacement
What would I given my patient with ADA deficiceny?
ADA (adenosine deaminase)
Intracellular
Protein targets for Guacher and Fabry are examples of ?
Intracellular protein targeting
Chaperone therapy?
Chemical chaperones assist in proper protein folding
Example of chaperone therapy?
mutant-alpha-galactosidase A
Fabry disease
Protein replacement mainly helps what kind of illnesses?
autosomal recessive
challenges of protein based therapy?
production delivery targeting immune cost
Farnesyl Transferase Inhibitors in Progeria is an example of?
Compensation of Functional defects with novel drugs
How do Farnesyl Transferase Inhibitors work in Progeria?
Prevent Lamin A/C protein product (Progerin) from sequestration at the nuclear membrane
Gene Therapy
Approaches? (3)
Non-viral (liposome, direct DNA)
Adenoviral (DNA virus)
Retroviral (RNA virus)
Retroviral Gene Therapy
Advantage?
Integrate into cell genome
Minimal host immune reactions
Retroviral
Disadvantage?
Insert limited to 7-8kb
Infect only dividing cells (cannot reach quiescent tissue)
Retroviral
Safety?
Risk of insertional mutageneis / germline integration
Retroviral
Efficiency?
Titers of retroviruses relatively low
Efficient at infecting dividing cells
Retroviral
Duration?
As these integrate into genomic DNA, the transgene can be passed to daughter cells
Adenoviral
Advantage?
Wide variety of cell types can be infected
Transgene insert size can be 35-36kb
Stable and easy to get high titers
Adenoviral
Disadvantage?
Does not integrate into cell genome
Expression can be very transient
Some risk of malignant transformation
Adenoviral
Safety?
Lower risk of insertional mutagenesis
Immune reactions can be severe
Adenoviral
Efficiency?
Can infect non-dividing cells
Higher titers are possible
Adenoviral
Duration?
Typically short lived effect; not passed to daughter cells
Non viral
Advantage?
Insert size can be very large
Could deliver mini-chromosomes
Minimal host immune response
Non viral
Disadvantages?
Low efficiency
Transient expression
Non viral
Safety?
Safest?
Does not integrate into host genome
Non Viral
Efficiency
Often degraded by cellular mechanism - so non specific uptake is inefficient process
Non Viral
Duration?
Typically short lived effect
Not passed to daughter cell lines
Gene therapy approaches include what two broad strategies?
In vivo - ex vivo
