Primerano- Genetics x5- Leah Flashcards Preview

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Flashcards in Primerano- Genetics x5- Leah Deck (99):
1

What distinguishes a polymorphism from a benign mutation?

-Both polymorpism and mutations represent a "variant" allele

-Polymorphisms are "variant" alleles carried by more than 1% of the population. (I.e. not just carried by a single person!)

-Mutations can be carried by a single person, or less than 1% of the population (Bottom line: % population carrying the variant determines polymorphism vs mutation)

2

What makes a locus polymorphic?

-A gene locus with more than 100 possible variations (alleles) is "polymorphic"

3

What makes a disease or phenotypic trait "monogenic"? What does it mean when a monogenic disease shows allelic heterogeneity? Locus heterogeneity?

-Mongenic: disease phenotype or trait can be caused by mutating a single gene. -Allelic heterogeneity: same or similar disease can be caused by multiple different mutations at the SAME locus.

-Locus heterogeneity: mutations at multiple locations may lead to the same disease

 

(A note about locus heterogeneity: DO NOT BE CONFUSED. This does not mean that multiple loci must be changed AT ONE TIME to lead to a disease, it just means that either path A, B, *OR* C may get you to disease A)

4

--What is an example of a trait that has monogenic inheritance?

--What are 3 examples of diseases with monogenic inheritance? Their inheritance patterns?

--Which of the three diseases have allelic heterogeneity? Locus heterogeneity?

-cell surface antigens (blood groups, HLA antigens)

-DMD (XR), CF (AR), PKU (AR)

-DMD and CF= allelic heterogeneity

-PKU= locus heterogeneity

5

What is allelic constitution? What are the four types of constitution?

-arrangement of different possible alleles at locus

1. SAME two HEALTHY alleles at locus = homozygous

2. Two DIFFERENT alleles at locus= heterozygous

3. Two different DISEASED alleles= heteroallelic

4. Two of the SAME DISEASED alleles= homoallelic

 

Bottom line: suffix --zygous = no disease; suffix allelic= diseased

6

What is the consequence of the F508 mutation on the CFTR gene?

The F455 mutation?

F508: constributes to severe (pancreatic insufficiency) form of CF)

F455: constributes to mild (pancreatic sufficient) form of CF

7

What are the five possible allelic constitutions in the CFTR gene?

-+/+: homozygous (healthy)

-F508/+: heterozygous (carrier)

-F508/F508: homoallelic (severe disease)

-F508/455: heteroallelic (mild disease)

-F455/455: homoallelic (very mild disease)

8

What is the difference between Duchenne and Becker Dystrophy?

What is this an example of?

Both cause muscular weakness :

-Duchenne: large out of frame dystrophin deletion --> complete loss of protein; severe disease and death at 18

-Becker: small in frame dystrophin deletion --> partial loss of protein; mild disease

Example of monogenic inheritance + allelic heterogeneity! (multiple possible alleles causing same or similar disease)

9

In addition to Duchenne/ Becker's Muscular Dystrophies, ______ ______ is an example of a disease with allelic heterogeneity. In addition to being classified as having "allelic heterogeneity", these diseases could also be called ________.

-CF (Remember; F508 and F455 mutated alleles both cause similar disease with F455 being less severe) -monogenic

-CF + DMD are MONOGENIC and have ALLELIC HETEROGENEITY!

10

What kind of stain is used to distinguish Duchenne from Becker's on muscular biopsy?

-immunofluorescence

-NO dystrophin in Duchennes

-LOWERED dystrophin in Beckers

11

Phenylketonuria results from failure to ________.

97% of cases are caused by a mutation in _______.

3% of cases are caused by mutations in OTHER enzymes.

This is an example of ______ ______.

-Convert phenylalanine to tyrosine

-97% = mutation in phenylalanine hydroxylase

-example of locus heterogeneity (also a monogenic disease because only ONE ENZYME must be lost to cause the disease!)

12

Type 1 PKU:

-gene affected?

-chromosome?

-dietary restrictions?

-phenylalanine hydroxylase

-chromosome 12

-restrict phenylalanine

13

Type 2 PKU:

-gene affected?

-chromosome?

-dietary restrictions?

-BH4 reductase

-chromosome 4

-restrict Phe, LDOPA, and 5HT

**UWORLD QUESTION**

14

Type 3 PKU: -gene affected? -chromosome? -dietary restrictions?

-Biopterin synthesis

-multiple possible loci

-restrict Phe, LDOPA, 5HT

15

Mitochondrial Inheritance:

-How many genes?

-What kinds of functions do these genes have?

-Describe the pattern of inheritance in mt. disease.

-Uworld likes to call diseases with mt inheritance an example of ?

-Primerano calls this an example of?

-Disease Example:

-37 genes

-oxphos, rRNA, tRNA

-mom to ALL offspring; dad to NO offspring -"heteroplasmy"

-"replicative segregation" (See picture on pg 5 of his notes)

-Leber Hereditary Optic Neuropathy

16

Many traits are determined by the interaction of multiple genes, meaning they have _______ inheritance.

_________ refers to all genes that infleunce the action of the gene in question, which can often explain incomplete penetrance/ variable expressivity.

-Polygenic inheritance

-Genetic background

17

What does it mean when a trait is said to have "multifactorial" inheritance?

What are some examples of these traits?

-Multiple genetic and environmental factors interact to give the trait

-Examples: intelligence, height, weight, Alzheimers, CVD, cancer etc.

18

Polygenic inheritance often leads to conditions with ______ & _________.

This can most often be explained by ______.

However, incomplete penetrance in Fragile X is explained by ______.

-incomplete pentrance

-variable expressivity

-most often due to multifactorial inheritance (more than one gene + environment)

-*genomic instability*/ *allelic heterogeneity* in Fragile X

19

Penetrance is the probabiltiy that _____?

What is the equation for penetrance? In "incomplete pentrance", what is said to determine the presence or absence of a trait?

-trait will be manifested in the presence of a given allele

-#cases with phenotype/# cases with genotype

-"either-or" phenomenon

-most often said to be determined by modifier gene (genetic interaction)

20

Incomplete penetrance is a characteristic of ______ inheritance.

On a pedigree, diseases with incomplete penetrance appear to ______?

-dominant inhertiance, recessive does not = incomplete penetrance

-appears to "skip" a generation

21

CF: complete or incomplete penetrance?

-COMPLETE

-genotype = 100% chance developing phenotype

(Remember, incomplete penetrance is possible in DOMINANT inheritance, CF is AR.)

22

Huntington's Disease: Complete or Incomplete Penetrance? What determines the age of onset?

-AD -COMPLETE penetrance with varying age of onset

-Age of onset inversely related to the number of trinucleotide repeats

23

Polydactyly, Brachydactyly, and Fragile X: Complete or Incomplete Penetrance?

-Incomplete

24

Retinitis Pigmentosa is an example of disease with _____ inheritance.

What genes are involved?

What does the disease cause?

-Polygenic inheritance

-Requires TWO DIFFERENT mutated genes (peripherin and ROM1 photoreceptor proteins

-Cause of retinal degeneration

25

Fragile X:

-Describe the prevalence

-most common HEREDITARY form of mental retardation

-2nd most common cause overall (#1 = trisomy 21) -1/1250 males

26

Fragile X:

-What is seen on cytology?

-secondary constriction on X chromosome (fragile site)

-site has frequent breakage and fails to condense during metaphase

**Note: this is not longer the diagnostic method of choice, but may be tested.

27

Describe a male with Fragile X:

Female X carrier?

Homozygous female?

MALES:

-mental retardation, delayed speech -large head, testes, ears, jaw -stubby hands

FEMALE CARRIER: -may be shy and have learning disorder

HOMOZYGOUS FEMALE: -not seen, Fragile X males don't mate

28

Fragile X:

Inheritance Pattern?

Penetrance?

Variation of phenotype in females is due to?

When do repeats "occur"?

-X linked dominant FMR1 mutation

-CGG trinucleotide repeats at the 5' region

-incomplete penetrance w/ % penetrance dependent upon sex

-variation in females due to EXTREME LYONIZATION

-repeats generated during meiosis + somatic events (i.e. some X chromosomes may have more repeats than others due to somatic events)

29

Incomplete penetrance is not a result of polygenic inheritance, but rather _______ in the case of fragile x.

-"allelic heterogeneity"

30

Fragile X pedigree:

-A phenotypically normal man who passes a disease allele to his offspring is called what?

-Compare the likelihood that his children will have disease vs his grandchildren. What is this called?

-nonpenetrant transmitting male (NPTM)

-granchildren more likely to have disease than children (trinucleotide expansion with each generation)

-Sherman paradox (^ likelihood of disease as you move down pedigree)

31

Fragile X: Describe the difference between a normal, premutated, and mutated allele.

-normal allele: less than 50 CGG repeats at 5'

-premutated: 50-200 repeats (low levels FMR1)

-more than 200 repeats (no FMR1 gene products)

32

How is Fragile X diagnosed?

Southern Blot: detects methylation and size expansions in larger mutations/ fully mutated alleles

PCR: discriminates small differences in pre-mutation alleles

33

What is the trinucleotide repeat in:

-Fragile X

-Huntingtons

-Myotonic Dystrophy

-Freidrichs These are all characterized by?

-Fragile X: CGG (See (C) a Gross Guy)

-Huntingtons: CAG (Hunt animals and put them in the CAGe)

-Myotonic Dystophy: CTG ("See (C) Tonic Gestures)

-Freidrichs: GAA (Genetic AtaxiA)

-genetic anticipation

34

Does genetic anticipation always cause "sherman phenomenon" on pedigree?

-NO

-Anticipation can be manifested by increased penetrance of disease with generation OR increased severity (i.e. lower age of onset as in Huntingtons)

bottom line: genetic anticipation does not always = increasing penetrance

35

What is ascertainment bias?

-False genetic anticipation

-Diseased individuals in early generations not detected --> causes apparent increasing penetrance

-(may be caused by lack of proper diagnostic tools etc)

36

Myotonic Dystrophy:

-inheritance pattern

-chromosome?

-repeat

-symptoms

-anticipation?

-autosomal dominant

-chromosome 19

-"See (C) Tonic (T) Gestures (G)"-- CTG

-myotonia, ptosis, cataracts, hypogonadism/ balding

-genetic anticipation (phenotypic worsening)

37

Expressivity:

Definition?

- How does this compare to penetrance?

-Expressivity: degree/ type of manifestation of a penetrant gene

-Penetrance: refers to the PRESENCE OR ABSENCE of manifestation of a diseased allele (either/or phenomenon)

38

Neurofibromatosis:

Inheritance pattern?

Gene involved?

CLASSIC EXAMPLE OF?

-Autosomal Dominant

-NF1

-classic example of VARIABLE EXPRESSIVITY

(same NF1 gene mutation can cause a variety of symptoms varying in severity)

39

Contrast mild v severe NF:

-mild: cafe au lait spots + neurofibromas

-severe: thousands of disfiguring neurofbromas, malignant brain tumors, mental retardation (variable expressivity)

40

Osteogenesis Imperfecta:

-inheritance pattern

-penetration

-expressivity

-classic symptoms?

-AD

-100% penetrance

-variable expressivity

-blue sclera, easily fractured, deafness

41

What is uniparental disomy?

-Both copies of a chromosome come from the SAME parent (i.e. two maternal copies of chromosome 15, no paternal copies)

-EUPLOID karyotype! (23 x 2 chromosomes)

42

What is genomic imprinting?

-Chromosome activated or inactivated in a sex-specific manner

43

Two diseases classically used to exemplify uniparental disomy and genetic imprinting?

What chromosome do these diseases affect?

Which disease causes an ANGRY demeanor?

A happy demeanor?

-Angelman Syndrome (AS) and Prader Wili Syndrome (PWS)

-chromosome 15

-ANGRY FAT BOY: PWS

-HAPPY PUPPET: AS

44

-Deletion explains _____% of AS/PWS.

Explain how deletion leads to PWS or AS.

70% occur via this deletion method:

-PWS: PATERNAL (P of PWS) c15 is deleted, maternal c15 is silent

-AS: MATERNAL (mom is an ANGEL) c15 is deleted, paternal c15 is silent

 

(silent= genetic imprinting)

45

Deletion accounts for 70% of PWS/AS.

How do the other 30% of PWS/AS cases occur?

-Inheritance of TWO paternal c15's and NO maternal (AS)

-Inheritance of TWO maternal c15's and NO paternal (PWS)

 

(uniparental disomy)

46

What is a quantitative trait?

What is the most common inheritance type of quantitative traits?

-Trait that can be numerically measured on a continuous spectrum by meters, grams, test scores, etc

-Multifactorial inheritance (genes + environment)

47

Examples of normal human traits determined by a variety of genes + environmental factors:

-skin/ hair color -weight, height -blood pressure -intelligence

48

How is a dichotomous trait different from a quantitative trait?

-Quantitative trait is measured on a continuous spectrum (super short --> super tall) -Dichotomous trait is EITHER present OR absent (cleft lip)

49

How can a dichotomous trait be described using a bell curve?

Give an example.

-Bell curve has THRESHOLD point at which a trait will manifest

-Ex: Pyloric Stenosis: curve based on low --> high liability of disease.

Threshold point on curve marks point where disease DOES OR DOES NOT present (either-or phenomenon)

Liability bell curve based on both genes and environment

50

List five human diseases that are "threshold diseases"

1. pyloric stenosis (risk 5x ^^ in males)

2. cleft lip and palate

3. NTD

4. CVD (genes + exercise diet etc)

5. Emphysema (a1 anti-trypsin + smoking)

51

Multifactorial Disease:

-apparent inheritance pattern

-what is the "gamma ratio"?

-family studies suggest inherited disease, but no apparent mendelian pattern exists -yr= prevalence in family/ prevalence in general population

52

Multifactorial Disease:

-risk of primary family members contracting same disease as affected individual

-risk of remote relatives?

How does this compare to autosomal dominant conditions?

-primary relatives have risk ~ square root of general population frequency (this makes literally no sense to me but it is what the notes say.)

-risk RAPIDLY DECLINES for remote family members

-In autosomal dominant traits, risk of remote family members ~50% of primary family member risk.

53

For multifactorial traits with sex- dependent features, when is the recurrence risk especially high?

-When proband (affected person the study starts with) is the LESS COMMONLY AFFECTED GENDER.

-I.e. female with a PREDOMINATELY MALE disease! (Suggests higher level of genetic liability)

54

Alzheimers:

Where are NF tangles found?

What are senile plaques caused by?

Genes required for APP processing?

-Tangles: cortex and hippocampus

-Plaques: Amyloid Precursor Protein ^^^ --> Amyloid deposits

APP processing: presenilin 1 & 2

55

When does early onset Alzheimer's occur and what is its inheritance pattern?

What mutations are associated?

-Before age 60

-AD

-mutations in APP or presenilin 1/2

56

Typical Alzheimer's is an example of what kind of genetic disease?

Early onset?

-Typical: multifactorial

-Early Onset: monogenic + locus heterogeneity (can be caused by presenilin 1 or 2, or APP mutation)

57

What is the "Alzheimer's Susceptibility" Gene?

What is its function?

Which type of Alzheimer's is it related to?

What are the most common types of mutations observed at this gene?

-ApoE

-Binds APP and effects its processing

-Related to both types of alzheimers (typical & early onset)

-missense amino acid mutations at sites: 112 and 158

58

How does ApoE effect the risk of alzheimer's?

-DOSE DEPENDENT

-ApoEe4 (bad type; rapidly binds APP) homozygote= 90% risk disease by 65

while heterozyogte = 45% risk

59

A person's ______ sets the range of possible _____, and the environment determines the specific _____.

-genotype= range of phenotype -environment determines specific phenotype

60

Define population genetics:

What does the Hardy Weinburg Equation allow calculation of?

Population genetics: Study of the frequency of alleles in a given population + the factors that maintain or alter said alleles

 

Hardy Weinburg: frequency of a given genotype, using frequency of given alleles

61

How is allele frequency determined (aka, p and q)?

In a population with only TWO alleles of a given gene, what is the sum of each allele's frequenct (p+q)?

-number of one allele type / total number of all alleles in population

-If only two alleles exist, p + q always equal 1.

62

What is the Hardy Weinburg equation?

 

(Will be given on school exam, but need to know this for boards.)

(p+q)^2= p^2 +2pq +q^2 = 1

....where:

p^2 is the frequency og a genotype homozygous for allele type 1

2pq is the frequency of a heterozygous genotype

and q^2 is the frequency of genotype homozygous for allele type 1

63

How is population genetics applied to forensic science?

-Probability of a match between two DNA samples is dependent on the frequency of alleles in a given population

(population frequency subgroups may also be applied: i.e. frquency of SCA in african americans in the US)

64

What is the Hardy-Weinburg LAW?

What five factors must be present to apply this law?

-Frequency of a genotype is based upon frequency of alleles in a given population & the frequency of genotype is constant among all generations

Requires:

1. random mating

2. trait present in LARGE population

3.negligible amount of mutation

4. negligible amount of selection

5. negligible amount of migration

65

Give an example of non-random mating that would make the Hardy-Weinburg law inapplicable:

-Genotype bb rarely mates due to given trait (retardation, infertility etc) --> bb will decline over time

66

How does consanguineous mating effect genotype frequency over time?

-Increases the number of homozygotes

-Decreases the number of heterozygotes

67

What is a stratified population?

-One in which certain groups do not mate with one another

i.e.: blacks with whites, royalty with non-royalty, Ashenkazi Jews must marry other Ashenkazi jews...

68

Assortive mating is choosing a mate based on_______.

Assortive mating is similar to _______ mating.

What changes in genotype frequency are observed in assortive mating?

-phenotype (intelligence, appearance, etc)

-consanguineous

-^^ frequency of homozygotes

69

Why must a large population be used in Hardy Weinburg genetics?

What is genetic drift?

-In small populations, one genotype may be transmitted entirely by chance= easier to have "genetic drift"

-genetic drift: establishment of a new alleles or allele frequencies

70

What factor might disproportionately RAISE an allele frequency?

LOWER frequency?

In cases of increased and decreased allele frequency, what is required to maintain hardy weinburg equilibrium?

-Raised by high rates of mutation

-Lowered by low rates of MATING in a trait that reduces fitness of an individual

 

(If rate of mutation = rate of loss, no change in frequency, Hardy Weinburg applies)

71

What is genetic fitness?

When calculating the rate of mutation in autosomal dominant disorders, what must be accounted for?

-genetic fitness is the likelihood of transmitting ones genotype to the next generation

-Autsomal dominant mutation rate must take into consideration the number of alleles lost by selection (poor genetic fitness)

72

Under what circumstances can spontaneous mutation rate for AD diseases be determined?

What equations are used?

 

**PLEASE NOTE: THESE EQUATIONS ARE GIVEN ON THE EXAM. DO NOT MEMORIZE BUT DO BE FAMILIAR!

-Only in populations that follow hardy weinburg law (rate of mutation= rate of loss of homozygote)

-s=1-f

-m=s x q

 

where....

s= selective disadvantage

f= fitness

m= mutation rate

q= mutant allele frequency

(He will even tell us what these variables mean. DONT MEMORIZE!)

 

73

For XR disorders with 0 fitness, how many alleles are lost at each generation?

1/3 of alleles lost every generation

74

A group of colonists do not have the same allele frequencies as a population they came from.

What is this called?

Why does it violate Hardy Weinburg equilibrium?

Founder affect

-HW equilibrium does not apply because it requires negligible amounts of MIGRATION.

75

Lake Maracaibo, Venezuela has a high frequency of?

Why?

What's the point?

Huntingtons; due to European founder effect

NOT IN HW EQUILIBRIUM!

76

What is the HW equation for X linked traits?

-females: normal- p2+ 2pq + q2 =1

-males: simplified to p + q = 1

(no "carrier" or pq genotype, only one X chromosome present)

77

How is risk determined for mendelian traits?

If carrier status is know: punnet square

If carrier status is NOT known: use population frequency + punnet square

78

Empiric risk is the probability of ____. 

How is it calculated?

 

 

-recurrence

-# affected individuals / # offspring

79

GENETIC DISEASE TREATMENT TBL SESSION:

How did the treatment effectiveness of the 57 most common genetic diseases change between the years 1993 and 2008?

-Large increase in "full response" 20 genetic diseases (previously 8) show full response to treatment

-BUT Still have 17/57 with little to no response.

80

GENETIC DISEASE TREATMENT TBL SESSION:

Four reasons we are unable to effectively treat genetic disease:

1. pathogenesis not understood

2. prediagnostic fetal damage

3. severe phenotypes less treatable

4. dominate allele affects more difficult to repair

81

GENETIC DISEASE TREATMENT TBL SESSION:

Methods for treating metabolic abnormalities (5)

1. avoidance of drugs / dietary restriction of nutrients

 2. replacement of substance whose synthesis is blocked (thyroid hormone)

3. Diversion: achieve task by alternative metabolic path (urea cycle disease)

4. Enzyme or Receptor inhibition

5. Depletion

82

GENETIC DISEASE TREATMENT TBL SESSION:

Many metabolic diseases result from failure to synthesize a product and subsequent precursor buildup. What is the prototypical disease of this type?

-PKU, cannot synthesize tyrosine, phenylalanine buildsup --> phenylketones form = motor and mental retardation + musty odor

83

GENETIC DISEASE TREATMENT TBL SESSION:

In PKU, why do abnormalities present AFTER birth?

In addition to protein, what subtrates are ultimately products of Phe?

Where is PAH normally found?

-Maternal PAH is protective in utero

-DOPA, melanin, neurotransmitters

-PAH mostly in liver, some in kidney

84

GENETIC DISEASE TREATMENT TBL SESSION:

What are the three pathways for Phe degradation?

1. Phe --> tyrosine --> fumarate + acetoacetate

2. Phe --> phenylpyruvic acid (1-transamination)

3. Phe--> Phenylethylamine (decarboxylation)

85

GENETIC DISEASE TREATMENT TBL SESSION:

Describe how diversion is used to treat urea cycle disorders

GIVE BENZOATE SUPPLEMENTS:

NH3 --> Glycine

Gylcine combines with benzoate supplement --> hippurate

Hippurate excreted in urine

(Nitrogenous waste excreted via alternative path!= DIVERSION.)

86

GENETIC DISEASE TREATMENT TBL SESSION:

Compare and contrast Hemophilia A and B

-XR, both clotting deficiencies

-A: factor 8 missing (most common)

-B: factor 9 missing

87

GENETIC DISEASE TREATMENT TBL SESSION:

Describe the dangers assc with giving purified clotting factors to treat hemophilia.

Describe potential benefits of treating with recombinant factor proteins.

-Purified blood products: ^^ cost, ^^ injections, ^^ infection risk, arthritis risk

-Recombinant proteins: cheaper, less injections, less infection risk

88

GENETIC DISEASE TREATMENT TBL SESSION:

What is "Z variant PI"?

-anormal a1 anti-trypsin (protease inhibitor- "PI")

-does NOT effectively inhibit elastase

-builds up in hepatocyte ER

-causes emphysema + cirrhosis

(^^ risk in smokers due to oxidaxtion of a met residue on PI)

89

GENETIC DISEASE TREATMENT TBL SESSION:

What three diseases are successfully treated with somatic gene  transplant?

What are two methods for somatic gene transplantation?

-Gaucher's, Hunter's, Hurler's (Lysosomal Storage Diseases)

-administer allogenic marrow cells

-Transduce PT's bone marrow cells with wild type gene

90

GENETIC DISEASE TREATMENT TBL SESSION:

Problem with germline gene therapy

-Can be used to alleviate disease suffering but also for eugenic purposes

-ETHICAL/ MORAL DEBATE.

91

GENETIC DISEASE TREATMENT TBL SESSION:

Major difference between somatic and germline gene therapy?

-In somatic therapy, transduced trait cannot be passed on to progeny.

(No potential for eugenics)

92

GENETIC DISEASE TREATMENT TBL SESSION:

Compare/ contrast en vivo and ex vivo gene therapy.

What is an example of en vivo gene therapy?

-en vivo: vector targeted to a tissue transfects cell in body

(i.e. viral vector targeted to liver in FIX treatment and in treatment of hypercholesterolemia)

-ex vivo: patient's cells taken out, transfected in culture, reintroduced

93

GENETIC DISEASE TREATMENT TBL SESSION:

Initial diseases chosen for gene therapy due to relative ease of gene replacement?

Why are dominant disorders harder to treat than recessive?

-diseases involing ONE gene and ONE organ

-in recessive disease, defective protein replacement is sufficient for treatment.

-in dominant disease, defective protein must be both REMOVED and REPLACED.

 

94

GENETIC DISEASE TREATMENT TBL SESSION:

-Constituitive vs Regulated Disease:

which is easier to treat?

-Consituitive genes are more easy to replace than those than have strict transcriptional regulation

95

GENETIC DISEASE TREATMENT TBL SESSION:

Why is there interest in new F.IX replacement therapy?

-inconvenience of frequent injections of purified clotting factors, risk of deleterious immune responses against the therapeutic protein & infection

-Purified proteins also ^^ $$$.

 

96

GENETIC DISEASE  TREATMENT TBL SESSION:

Which vectors have been used in FIX gene therapy and what were the preferred target tissues.?

-adenovirus

-adeno assc virus (AAV)

-lentivirus

 

-muscle and liver both targeted; liver = better outcome

97

GENETIC DISEASE TREATMENT TBL SESSION:

Why is liver the preferred target for F. IX gene therapy?

  • FIX is naturally produced in the liver
  • Hepatocytes have more efficient secretion machinery than myocytes
  • The liver-directed gene transfer prevents subsequent antibody and CD8+ T cell responses

98

GENETIC DISEASE TREATMENT TBL:

What are the immune responses encountered for injected (in vivo) adenovirus and AAV gene therapy vectors? (3)

 Differences between Adenoviral and AAV vectors?

1. antibody binding and elimination of the vector particles

             2. direct stimulation of innate immunity pathways by vector particles

3. cell-mediated adaptive immunity can be responsible for the elimination of vector transduced cells

 

AAV vectors = LEAST immune activation!!!

99

GENETIC DISEASE TREATMENT TBL:

Why is F. IX a candidate for gene therapy?

-phenotype is attributable to the lack of a single protein

-gene is small and easily inserted into vectors