Treatment of Genetic Disease Flashcards
Majority of metabolic diseases manifest ________ inheritance.
autosomal recessive
Explain treatment of metabolic diseases:
Majority of metabolic diseases manifest autosomal recessive inheritance.
Newborn screening (done by heel stick test on ~all newborns) is done to diagnose early or pre-clinical disease in newborns and allow for early therapy, before permanent morbidity occurs.
General Uses and Indications: Diagnosed metabolic diseases where disease is due to deficiency of essential compound(s) and/or accumulation of toxic compound(s). Many of these are in amino acid catabolic pathways ! requires dietary restriction of > 1 amino acids.
Benefits: Effective in many cases, ‘leaky’ mutations can have relatively liberal diets.
Problems: l_ifelong compliance_, expensive, need trained nutritionist, need to maintain growth, illness can lead to secondary metabolic crises, can cause fetal damage, long-term prognosis on therapy not always known
Explain the treatment of mutant protein disorders?
General indications: Can be proposed for conditions where the genetic mutation causes a protein abnormality that is amendable to therapy by pharmacologic manipulation and/or protein replacement therapy (PRT).
Approaches:
- Replace extracellular protein
- Replace intracellular protein
- Target intrecellular protein
- Co-factor administration
Benefits: Can be quite effective in correcting enzyme deficiencies, especially when the targeted protein is needed in the plasma/serum (extracellular).
Problems: Expensive, Delivery of injected (extracellular) protein to specific organs and/or intracellular compartments is challenging, risk of immune response to recombinant protein, delivery across blood-brain barrier is challenging (neurological symptoms if present, often do not improve), protein replacement does not always correct existing cellular/tissue damage.
What are some examples:
Protein replacement therapy for alpha-1 antitrypsin deficiency and Fabry disease.
Gene therapy approaches
Retroviral
This method uses RNA viruses and can integrate into cell genome with minimal host immune reaction. A disadvantage is that the insert size of the transgene is very small (7-8kb) and it can only affect DIVIDING CELLS. Also, there is a risk for insertional mutagenesis (or integration into the germline).
Since these integrate into the genome, the transgene can be passed to daughter cellls.
Adenoviral
This method uses DNA viruses and can infect a wide variety of cells. The transgene size is a little bit bigger (35-36kb) and this one does NOT INTEGRATE into the genome. However, the expression can be transient (short) and there is risk of malignant transformation.
The risk for insertional mutagenesis is very small but immune reactions can be severe.
This one can infect NON-DIVIDING cells, and is not passed to daughter cells.
Non-viral
This method used liposomes or direct DNA insertion of very large size. Infact, it could even deliver mini-chromosomes with minimal host immune response.
A disadvantage it is that it has a low efficiency and a transient expression.
No risk of integrating into the host genome, so might me the SAFEST.
Often degraded by cellular mechanisms.
Farnesyl Transferase inhibitors
Showing promise in Lamin A/C mutations in Progeria, a premature aging syndrome. Lamin A/C mutation leads to a mutant lamin A/C protein (‘progerin’) that is targeted to the nuclear membrane by Farnesyl groups. Pathological effects at nuclear membrane. Farnesyl transferase inhibitors appear to reduce progerin sequestration at the nuclear membrane
How does Imatinib (Gleevac) treats chronic myelogenous leukemia?
Chronic myelogenous leukemia where a chromosome 9:22 translocation joins parts of two genes (BCR and ABL) into a fusion gene–> fusion transcript–>fusion protein called BCR-ABL that can be inhibited by Imatinib.
