Exam 2: Lecture 34 Flashcards
(27 cards)
1
Q
Augmentation Therapy: Enzyme Replacement Therapy
A
- typically IV, sometimes intramuscular
- replace deficient enzyme
- used in lysosomal storage disorders ( MPS, Fabry, Pompe, Gaucher)
2
Q
What is augmentation therapy?
A
- loss of normal protein function–> replace protein/ enzyme or enhance protein function
- Replace gene–> gene therapy
- enzyme replacement therapy
- organ or bone marrow transplant
- enhance production of the protein
3
Q
What are the limitations of Enzyme Replacement therapy
A
- may not penetrate certain tissues, especially BBB (blood brain barrier)
- expensive!!!!
- not a cure; need it for life (biweekly or weekly)
- may need central lines
4
Q
What are the risks of enzyme replacement therapy?
A
- hypersensitivity reactions/ anaphylaxis ( body may recognize it as foreign)
- ## patients often develop antibodies to the ERT (may need immunomodulation)
5
Q
Augmentation Therapy: Solid organ transplants
A
- types: liver and kidney transplants
- benefits: provides enzyme replacement for life
- transplants helps stabilize patients
6
Q
What are the limitations of organ transplants
A
- only provides partial replacements–> its only that organ
- toxic metabolites can still be made in other tissues
7
Q
What are the risks of solid organ transplants?
A
- high morbidity
- immunosuppressive drugs can lead to infections
- thrombosis and other complications from surgery
- rejection
8
Q
Organic acidemia
A
- toxic organic acids are made
9
Q
Augmentation Therapy: Organ Transplant for Methylmalonic acidemia
A
- organic acidemia with high risk for metabolic decompensation with metabolic strokes –> do liver or kidney transplant
- Benefits: can eat more protein, less risk for decompensation and strokes
- limitations: other tissues continue to make MMA; small risk for metabolic acidosis, stoke; if only liver transplant, will need kidney transplant later; typical transplant complications
10
Q
When is a Hematopoietic stem cell transplant (HSCT) conducted? - for what diseases?
A
- Hematopoietic stem cell transplant
- for hematologic diseases: thalassemias and other cytopenias
- immunodeficiencies
- lysosomal storage diseases ( MPS 1, Krabbe disease)
11
Q
How do you conduct a HSCT?
A
- bone marrow transplant; can be harvested from peripheral or umbilical cord blood
- replacing recipients bone marrow with donor’s stem cells
1) ablate the recipients bone marrow (drugs or chemotherapy)
2) induce immunosuppression to allow for infused stem cells to engraft
12
Q
Describe HSCT with Hurler Syndrome patients
A
- HSCT results in clinical improvement of somatic manifestations and cognitive function of it is completed under 2 y/o (after 2, too much neurological issues)
- may cause morbidity/ mortality dues to: immunosuppression, medication side effects, and Graft vs Host
- doesn’t fix everything, skeletal morbidities continue
13
Q
Augmentation Therapy: Gene Therapy Methods (2)
A
- in vivo: gene put in virus and virus injected in the body
- ex vivo: stem cells removed from patient; genes placed in stem cell; cells put back in
14
Q
What are the vectors used for gene therapy?
A
- use a vector–> depends on the size, what tissue, target cell, how it will deliver the gene, and the antibody status
- DNA viruses used: adenovirus, adeno-associated virus (small, nonpathogenic), herpesviruses
- RNA viruses (retroviruses): lentivirus, gamma-retroviruses
- lipid nanoparticle ( with mRNA)
15
Q
What are the methods for integration for gene therapy?
A
- with mRNA–. pop it in the cell
- retroviruses will integrate it into the genome
- other viruses: deliver DNA to nucleus , no integrates, can deliver gene-editing tool, “homology guided” integration of DNA
16
Q
What is spinal muscular atrophy?
A
- cuase by deletion or mutations in SMN1 gene
- SMN2 gene is a pseudo gene–> milder form, less severe
- causes sever hypotonia and never develop any milestones
- common type–> may develop some milestones like keeping head up, but not sit or roll
17
Q
Describe the gene therapy for spinal muscular atrophy
A
- Zolgensma
- SMN1 transgene in an AAV9 virus capsid
- 1 time injection, under 2 yrs
- improvement in muscle and respiratory areas
- no serious adverse events, deaths, or discontinuation
- Spinraza –> targets SMN2….. to increase mRNA transcripts that include exon 7, so it is functional (intrarectal injections, ongoing)–> for SMA type 1
18
Q
Enhancing protein transcription
- example with DMD
A
- DMD (X linked); caused by deletion of an exon or exons leading to a truncated protein
- Treatments: Etepelrisen
- exon skipping: skips exon(s) with the deletion/mutation; hides it so it is ignored…. cells continue to produce the protein… may be shorter, but mostly functional
-cells produce a shorter but functional dystrophin (effective in 13% of patients with deletion exon 51)
19
Q
How do you prevent harmful substances from building up?
A
- dietary interventions
- medications
- small molecules
- substrate reduction therapy
20
Q
Examples of Dietary interventions with MSUD or MMA
A
- in metabolic conditions: use dietary treatments
- restriction of specific amino acids –> ex. MSUD (maple syrup urine disease): restriction of leucine or MMA/PA: restriction of branched chain AA
- must provide other AA via formula for normal growth development with other AA
- may have growth issues, nutritional deficiencies, affects quality of life
- cannot eat meat or diary
21
Q
How are drugs used to Block pathway (Intervention) for Tyrosinemia type 1?
A
- in metabolic conditions–. can block pathways
- ex. Tyrosinemia type 1–> problem with the breakdown of tyrosine
- toxic metabolites that builds up called succinylacetones–> causes corneal crystals, liver damage, cirrhosis of the liver
- Treatmennt: blocks pathway before it gets to succinylacetone with drug, Nitisinone
22
Q
How are diet and drugs used to treat PKU?
A
PKU–> PATIENTS CANNOT BREAKDOWN PHENYLALANINE
- if untreated can cause cognitive, psychologic, and developmental issues
- Treated with diet by restricting phenylalanine
- Drug: Palynziq –>breakdown Phe through a different pathway
- Patients can eat a normal diet including Phe
- side effects: high risk of anaphylaxis
23
Q
Describe rug intervention for urea cycle disorders
A
- scavenger medications
- alternate way to rid body of nitrogen waste so less ends up in urea cycle
- less chance of hyperammonemia
24
Q
Describe substrate reduction therapy role in the treatment of Gaucher disease
A
- use in gauche disease ( lysosomal storage disease–. accumulation of glycoceramide due to not having glycoceramidase)
- Miglustat –> inhibits the production of glycosylceramide
- N-butyldeoxynojirimycin (Miglustat) –> oral therapy, can pass BBB, approved for adults with mild to moderate type1
25
What is the role of small molecules in cystic fibrosis treatment?
- small molecules that bind to a target site in a protein--> may block the function of the protein
- Ex. CF --> cftr channel not working properly and G551D mutation--> chloride channel not opening
- drug can bind to specific part of the channel to help keep it open
26
What is Tuberous sclerosis?
- autosomal dominant disorder; non- invasive benign tumor like lesions (hamartomas) develop in multiple organ systems, including the brain, heart, skin, kidney, lung and liver
- causes by TSC1 and TSC2, encodes proteins that regulate cell proliferation and differentiate (hyperactivation of mTOR pathway)
- experiences seizures, developmental and behavioral issues
27
What is the role of small molecules in Tuberous sclerosis treatment?
- mTOR inhibitors--> inhibiting this pathway
- decreases the tumors on the kidneys, seizures, skin problems, growth on the brain
