Emerging Treatments Flashcards
What is the largest group of genetic diseases?
Inborn errors of metabolism
What causes inborn errors of metabolism?
Defects of single genes that code for enzymes that facilitate conversion of substrates into products
What is the main problems with the inborn errors of metabolism?
There is an accumulation of substances that are not converted into products that may be toxic or interfere with normal function
What are four examples of diseases caused by inform errors of metabolism?
Maple syrup urine disease
MCAD Deficiency
Phenylketonuria (PKU)
Homocystinuria
What pathways do inborn errors of metabolism effect?
carbohydrates
fatty acids
proteins
What happens in phenylketonuria?
There is no phenylalanine hydroxylase meaning phenylalanine is no longer converted into tyrosine and is converted into phenylketones instead
What can untreated PKU lead to?
Major cognitive impairement
Behavioural difficulties
Lack of melanin so fairer skin and hair
Recurrent vomiting
What is used to treat PKU?
Tyrosine supplements in diet
Why are patients with PKU advised to keep a low protein diet?
Phenylalanine is an amino acid found in protein, so given PKU patients are advised to have a low protein diet to avoid unnecessary buildup as they struggle to degrade it
What are some symptoms of Haemophillia?
Controlled bleeding
Bleeding into joints and brain
Internal bleeding
How is haemophillia treated?
By replacing the missing clotting factors isolated from human blood serum, 8 and/or 9
What is important to know before trying to treat through diet and replacement?
The biochemistry behind the condition as the treatment is not mutation specific
What are four other conditions which can be treated by replacement?
Growth hormone deficiency
Fabry disease
Pompe disease
What are the four general stages of drug development?
- Discovery/preclinical
- Lab based testing
- Clinical testing - in 3 phases
- Approval by the regulatory bodies
What happens in phase 1 of clinical testing?
Tested on healthy volunteers, with a sample size of <100
What happens in phase 2 of clinical testing?
The drug is tested to check the therapeutic effect on patients with the condition, 100-300 people
What happens in phase 3 of clinical testing?
Large scale therapeutic trials with 2000-3000 patients
Who tests and approves drugs in England?
The National Institute for Health and Care Excellence
What is the purpose of protein-targeting therapies?
They try to normalise the function of mutant proteins
What is a pharmacological chaperone?
A drug which serves as molecular scaffolding in order to stabilize mutant proteins and cause them to fold correctly
What condition is migalastat used to treat?
Fabry disease
What are pharmacological modulators?
They are receptor agonists / antagonists which can act as ion channel activators and blockers
What condition is Ivacaftor used to treat?
Cystic fibrosis
What is combination therapy?
When a protein chaperone and modulator is used as the problem could be fixed with both
What is an example of a case where combination therapy would be useful?
When you have a defective chloride ion channel in CF resulting from one mutations that lead to misfolding
What is a non-sense mutation?
When a stop codon is inserted into the middle of the gee, preventing the complete read-through of the instructions for a complete protein to form
How does stop codon read through therapy work?
When the therapy can recognise a mutated stop signal which differs from the normal one, and encourages the cell to ignore the stop codon
What condition is Ataluren used to treat and what kinda of treatment is it?
Stop codon read through therapy for Duchenne Muscular Dystrophy
What are the four methods of small molecule treatment?
- Stop codon read through therapy
- Pharmacological Modulators
- Pharmacological Chaperones
- Combination therapy
What does in vitro mean?
In Glass
What is meant by gene therapy?
The therapeutic delivery of nucleic acid into a patients cells as a drug to treat disease
What does in vivo and ex vivo mean?
In the living and out the living
What are three reasons that gene therapy is very difficult to achieve in practise?
Achieving specificity
Getting therapy to right place
Maintaining expression once it is in the right place
What is done in gene therapy when you have a recessive disease?
You replace the defective gene
What is done in gene therapy when you have a dominant disease?
Delete defective gene
What is meant by spindle transfer?
Where the nuclear DNA is transferred to another healthy egg cell leaving the defective mitochondrial DNA behind
Is mitochondrially inherited disease therapy in vivo or in vitro?
In vitro
What does virus gene therapy involve?
The use of an engineered virus to carry therapeutic genes
Give examples of conditions that virus gene therapy has been used to treat?
AAV
Adenovirus
Lentivirus - HIV
Vaccinia Virus
Why can virus gene therapy be useful for patient with SCID?
SCID can sometimes be treated using a bone marrow transplant, however it is not possible for all children as 50% of patients with SCID cannot find a donor match
What are CAR-T cells?
Chimeric Antigen Receptor T cells
How does CAR-T cell therapy work?
T cells are genetically engineered to express chimeric antigen receptors bound to MHC, which are speicifially directive towards antigens on patients tumour cells - this means the cancer cells are killed and attacked
What thpe of antibodies recognises cancer cells using CAR-T cells?
scFv = single chain fragment variable
What are some of the side effects of CAR-T cell therapy?
Cytokine release syndrom and neurological damage
How does in vivo supplement therapy work?
When patients lack a functional copy of the gene, they can use a virus to carry a working copy into the cells
What are anti-sense oligonucleotides?
Small sections of mRNA which bind to target mRNA and cause it to be degraded - preventing ghr peotein being transcribed properly
What type if diseases is in vivo known down therapy useful for?
In diseases caused by a gain of function
What is exon skipping therapy?
Involves the use of oligonucleotides to skin disease causing exon, with the useful RNA being put back into the reading frame so active protein is still made
What can happen in exon skipping therapy when given to patients with duchenne muscular dystropy?
Removal of thr mutant exon can cause DMD to become BMD
What are some future possible gene therapies?
CRISPR-Cas 9
What are the disadvantages of using CRISPR-Cas9?
Cannot target large changes like large deletions of triplet expansions
One form of SCID (severe combined immunodeficiency) is caused by a lack of Adenine deaminase (ADA) in haematopoietic stem cells. This condition is often treated by bone marrow ransplant. In some patients this is not possible what genetic approach could be used to treat this condition?
Ex vivo gene therapy
Phenylketonuria (PKU) is an autosomal recessive disease caused by lack of phenylalanine hydroxylase (PAH). Some of the mutations in PAH prevent it from folding properly. Other mutations reduce the activity of the enzyme. Which approaches might be successful in treating the disease caused by these two types of mutation.
Pharmacological chaperones
Familial Mediterranean fever is an autosomal dominant disease caused by a point mutation in FMF gene. Which approaches might be successful in treating this disease?
Knowndown approach
Marsili Syndrome is an autosomal dominant disease caused by a mis-sense mutation, in this disease the mutation is the (a point mutation) in the ZFHX2 gene. What approach might be successful in treating this disease ?
Knockdown (antisense) approach - disease is dominant and caused by a protein with a gain of function so thr activity of this protein needs to be blocked
McArdle Disease is an autosomal recessive condition caused by mutations in glycogen phosphorylase, muscle associated (PYGM). PYGM is small enzyme . One of the most common mutations is a nonsense mutation (a premature stop codon) caused by the change of a single nucleotide. What approaches might be useful for treating this disease ?
Stop codon read through therapy as it is caused by a premature stop codon
