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Investigation Of Human Disease > diagnosis and treatment of muscular dystrophies > Flashcards

diagnosis and treatment of muscular dystrophies Flashcards

1
Q

Describe the first symptoms of Duchenne Muscular Dystrophy (DMD)

A

First symptoms include Gower’s manoeuvre, waddling gait, and enlarged calves.

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2
Q

What is the significance of elevated Creatine Kinase (CK) levels in DMD diagnosis?

A

Elevated CK levels are a common finding in DMD, but they are not specific to skeletal muscle issues.

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3
Q

How is genetic testing used in the diagnosis of muscular dystrophies?

A

Genetic testing is used to identify faulty genes through PCR and sequencing, although it can be expensive, time-consuming, and challenging for unclassified cases.

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4
Q

What is the purpose of a muscle biopsy in diagnosing muscular dystrophies?

A

A muscle biopsy involves removing a small tissue sample for histological analysis to aid in diagnosis.

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5
Q

What is Gower’s manoeuvre in the context of DMD diagnosis?

A

Gower’s manoeuvre is a characteristic way of rising from a sitting position seen in individuals with DMD.

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6
Q

Define Creatine Kinase (CK) and its role in diagnosing muscular dystrophies.

A

CK is an enzyme found in muscles, and elevated levels in blood tests can indicate muscle damage, though it is not specific to muscular dystrophies.

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7
Q

How are elevated Creatine Kinase (CK) levels detected in DMD patients?

A

CK levels are measured through blood tests, with significantly elevated levels observed in DMD patients.

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8
Q

Describe the challenges associated with genetic testing in diagnosing muscular dystrophies.

A

Genetic testing for muscular dystrophies can be expensive, time-consuming, and may not always provide clear results, especially in unclassified cases.

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9
Q

Describe the histological features of muscular dystrophies.

A

Increased endomysial connective tissue, variable fiber size, centrally located nuclei, infiltration.

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10
Q

What can be identified through immunostaining in muscular dystrophies?

A

Defective genes such as dystrophin deficiency and mutations in the laminin a2 chain.

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11
Q

Describe the process of creating chimeric mice for research purposes.

A

Chimeric mice are generated by injecting embryonic stem cells carrying a targeted mutation into a host blastocyst.

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12
Q

What is one potential therapy for muscular dystrophies mentioned in the content?

A

Restoring the missing protein is mentioned as a potential therapy for muscular dystrophies.

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13
Q

Describe a potential therapy for muscular dystrophies involving restoring the missing protein using virus-mediated gene transfer.

A

Restoring the missing protein in muscular dystrophies can be attempted through virus-mediated gene transfer.

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14
Q

What are some problems associated with the approach of restoring missing protein in muscular dystrophies through virus-mediated gene transfer?

A

Toxic side effects in humans, difficulty in targeting skeletal muscle spread over the whole body, inflammatory response to transplanted myoblasts, and immune response to gene and virus product are some problems.

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15
Q

How does Adeno-associated vector (AAV) play a role in potential therapies for muscular dystrophies involving restoring the missing protein?

A

AAV is a small single-stranded DNA virus that can efficiently transduce skeletal muscle after systemic delivery and is less immunogenic compared to other viruses.

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16
Q

Define the limitation of Adeno-associated vector (AAV) in potential therapies for muscular dystrophies involving restoring the missing protein.

A

AAV can only carry a small DNA size (<5kb) and does not integrate into the genome.

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17
Q

What are the solutions proposed for potential therapies for muscular dystrophies involving restoring the missing protein using Adeno-associated vector (AAV)-mediated gene transfer?

A

Using minigenes of dystrophin containing the minimal requirements for muscle function, which can convert Duchenne type into milder Becker type of muscular dystrophy, and conducting human phase I/II trials to assess the level of gene transfer into muscle.

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18
Q

Describe potential therapies for muscular dystrophies involving restoring missing proteins through read-through stop codon strategies using aminoglycoside antibiotics.

A

The strategy involves using aminoglycoside antibiotics to interfere with translation fidelity of the ribosome, introducing point mutations into the RNA to correct stop codon nonsense mutations.

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19
Q

What was observed in mdx mice regarding the restoration of dystrophin levels using antibiotics?

A

Some antibiotics were able to restore dystrophin levels up to 20% in mdx mice, which are dystrophin-deficient due to a point mutation in exon 23.

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20
Q

What is PTC 124 and how does it relate to potential therapies for muscular dystrophies?

A

PTC 124 is a small molecule developed as an aminoglycoside antibiotic analogue to bypass nonsense stop mutations in the RNA, with efficiency in restoring dystrophin similar to aminoglycosides.

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21
Q

How successful were human trials with Gentamycin for muscular dystrophies?

A

Human trials with 7.5 mg/kg body weight Gentamycin proved unsuccessful and had the likelihood of toxicity.

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22
Q

Define the outcome of the phase 2b clinical trial for Duchenne muscular dystrophy involving PTC Therapeutics.

A

The trial did not show a significant improvement after 48 weeks, leading to the termination of a $100 million deal with another company to pursue the drug.

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23
Q

How did Ataluren progress in terms of approval and market authorization for treating muscular dystrophies?

A

Ataluren received a positive opinion from the European Medicines Agency (EMA) in May 2014, gained market authorization in August 2014, and was on the market in several European countries by December 2014 under the trade name Translarna.

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24
Q

What was the FDA’s response to PTC Therapeutics’ new application for ataluren in February 2016?

A

The FDA declined to accept the application based on a clinical trial where ataluren missed its primary endpoint; PTC appealed, but the FDA declined again in October 2016.

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25
Q

Describe the Managed Access Agreement (MAA) for Translarna agreed upon by NHS England in July 2016.

A

NHS England agreed to provide reimbursed patient access to Translarna in England via a five-year MAA, allowing patients to access the drug.

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26
Q

What are the limitations of potential therapies like PTC 124 for muscular dystrophies?

A

These therapies are restricted to muscular dystrophies caused by a nonsense mutation and may not be equally effective with every stop.

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27
Q

Describe the concept of restoring missing protein by exon skipping in the context of muscular dystrophies.

A

Explain how some patients with muscular dystrophies may have dystrophin positive revertant fibres due to secondary somatic mutations or alternative splicing events.

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28
Q

What are dystrophin revertant fibres in the context of muscular dystrophies?

A

Fibres that stain in some patients with muscular dystrophies and are considered rare events, potentially restoring the missing protein.

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29
Q

Define exon skipping as a potential therapy for muscular dystrophies.

A

Explain the process of skipping certain exons during mRNA processing to restore the open reading frame and produce functional proteins.

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30
Q

How does exon skipping contribute to potential therapies for muscular dystrophies?

A

Describe how skipping specific exons can help in restoring the missing protein, such as dystrophin, to improve muscle function.

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31
Q

Describe the role of normal splicing of DMD exons in the context of muscular dystrophies.

A

Explain how correct splicing of exons is essential for the proper translation of pre-mRNA into functional dystrophin protein.

32
Q

What is the significance of dystrophin exon boundaries in the treatment of muscular dystrophies?

A

Understanding the specific boundaries of dystrophin exons is crucial for developing therapies like exon skipping to restore the missing protein.

33
Q

How can understanding dystrophin exon boundaries aid in potential therapies for muscular dystrophies?

A

Explain how knowledge of exon boundaries can help in designing strategies like exon skipping to target specific regions for restoring functional dystrophin.

34
Q

Define the term ‘revertant fibres’ in the context of muscular dystrophies.

A

Describe the fibers that can stain in patients with muscular dystrophies, potentially indicating a rare event of secondary somatic mutations or alternative splicing events.

35
Q

How do revertant fibres play a role in potential therapies for muscular dystrophies?

A

Explain how the presence of revertant fibres in some patients may offer insights into mechanisms like secondary somatic mutations or alternative splicing events for restoring the missing protein.

36
Q

Describe the process of exon skipping as a potential therapy for muscular dystrophies.

A

Explain how skipping specific exons during mRNA processing can help in restoring the open reading frame and producing functional proteins like dystrophin.

37
Q

What is the role of exon skipping in potential treatments for muscular dystrophies?

A

Explain how the strategy of exon skipping aims to restore the missing protein by skipping certain exons to enable the production of functional proteins like dystrophin.

38
Q

How can understanding the concept of exon skipping benefit the development of therapies for muscular dystrophies?

A

Describe how knowledge of exon skipping mechanisms can lead to the development of targeted treatments for restoring missing proteins in conditions like muscular dystrophies.

39
Q

Describe the process of exon skipping in the context of DMD.

A

Exon skipping involves skipping specific exons during pre-mRNA splicing to restore the reading frame and produce a functional protein.

40
Q

What is the consequence of disruption of the reading frame in DMD?

A

Disruption of the reading frame in DMD leads to a non-functional Dystrophin protein.

41
Q

Define ORF in the context of genetic mutations like in DMD.

A

ORF stands for Open Reading Frame, which is the sequence of nucleotides that can be translated into a protein.

42
Q

How are antisense oligonucleotides (AON) utilized in research related to DMD?

A

Antisense oligonucleotides are used to target specific genes or splice sites to modulate gene expression or splicing, such as in exon skipping therapies for DMD.

43
Q

Do deletions of specific exons in DMD always result in non-functional Dystrophin?

A

No, deletions of certain exons can lead to a shorter but functional Dystrophin protein, as seen in Becker Muscular Dystrophy (BMD) cases.

44
Q

Describe the role of splicing in the process of gene expression.

A

Splicing is the process of removing introns and joining exons in pre-mRNA to generate a mature mRNA transcript for translation.

45
Q

What modifications were introduced to stabilize the original AONs used in DMD research?

A

Modifications were introduced to stabilize the original AONs that were proven to be unstable in research related to DMD.

46
Q

How was the mdx mouse model utilized in testing the efficacy of splice site targeting in DMD research?

A

The mdx mouse model was used to test the efficacy of targeting splice sites at intron-exon boundaries to prevent splicing, as part of research on DMD therapies like exon skipping.

47
Q

Describe the process of exon skipping as a therapy for D.

A

Exon skipping involves using molecules like AONs to skip specific exons in the dystrophin gene, allowing the production of a shorter but functional dystrophin protein.

48
Q

What is the advantage of exon skipping in DMD treatment?

A

The advantage is that over 60% of individuals with DMD could potentially benefit, especially those with out-of-reading-frame mutations within the dystrophin gene.

49
Q

What is the disadvantage of exon skipping in DMD treatment?

A

The disadvantages include the need for specific AONs for each patient mutation, limited lifetime of AONs in tissues requiring repeated administration, uncertainty about efficient systemic delivery, and challenges in targeting multiple exons simultaneously.

50
Q

Define AON in the context of DMD treatment.

A

AON stands for antisense oligonucleotides, which are molecules used to induce exon skipping in the dystrophin gene to restore the reading frame and produce functional dystrophin protein.

51
Q

How does Eteplirsen function in DMD treatment?

A

Eteplirsen is a phosphorodiamidate morpholino oligomer that targets exon 51 of the dystrophin gene, inducing exon skipping to restore the reading frame and produce functional dystrophin protein.

52
Q

Describe the outcome of the first clinical trials of Eteplirsen for DMD.

A

The trials showed an increase in dystrophin expression up to 18% of healthy levels, but with high variability among patients.

53
Q

What was the FDA’s decision regarding Eteplirsen in 2016?

A

The FDA approved Eteplirsen in September 2016 for DMD treatment, while rejecting another drug (Drisapersen) due to side effects and inefficiency in increasing dystrophin expression.

54
Q

How often is Eteplirsen administered in DMD treatment?

A

Eteplirsen is systemically injected on a weekly basis for DMD treatment.

55
Q

What is the cost of treatment with Eteplirsen per year?

A

Treatment with Eteplirsen costs $300,000 per year for DMD patients.

56
Q

Describe the concept of upregulation of compensatory proteins in the context of potential therapies for muscular dystrophies.

A

Upregulation of compensatory proteins involves increasing the expression of proteins like utrophin or integrin to compensate for the deficiency of proteins like dystrophin in muscular dystrophies.

57
Q

What is the advantage of upregulating utrophin as a potential therapy for muscular dystrophies?

A

Utrophin will not be recognized by the immune system, unlike dystrophin, reducing the risk of immune response.

58
Q

What was the outcome of injecting mdx mice with virus-mediated utrophin expression?

A

58% of muscle fibers showed sarcolemmal expression of utrophin, and increased utrophin expression restored dystrophin associated components of the DGC.

59
Q

How does overexpression of 1 INTEGRIN impact dystrophic symptoms in mdx mice?

A

Overexpression of 1 INTEGRIN ameliorates dystrophic symptoms in mdx mice.

60
Q

Define the role of AGRIN in potential therapies for muscular dystrophies.

A

AGRN overexpression restores dystrophic symptoms in dy/dy mice, which lack the laminin a2 chain.

61
Q

Describe the role of utrophin in muscle fibers during development.

A

Utrophin is normally present in muscle fibers during development but is replaced by dystrophin in perinatal development after birth.

62
Q

What is the significance of utrophin being naturally upregulated in dystrophin deficiency?

A

Utrophin being naturally upregulated in dystrophin deficiency provides a potential therapeutic target for muscular dystrophies.

63
Q

How does upregulation of compensatory proteins like utrophin contribute to potential therapies for muscular dystrophies?

A

Upregulation of compensatory proteins helps compensate for the deficiency of proteins like dystrophin, offering a potential treatment strategy for muscular dystrophies.

64
Q

What is the percentage of muscle fibers expressing dystrophin 10 weeks after bone marrow transplantation?

A

<1%, 1%, 10%

65
Q

Describe the aim of the compound Ataluren (PTC124) in the context of the clinical trial mentioned in the content.

A

Stop mutation read through

66
Q

What is the purpose of AVI4658 in the clinical trial described in the content?

A

Exon 51 skipping

67
Q

Define the goal of Coenzyme Q10 in the clinical trial related to skeletal muscle regeneration.

A

Improve muscle strength

68
Q

How is EGCg (green tea extract) intended to impact muscle condition in the clinical trial mentioned?

A

Improve muscle condition

69
Q

Do you know the main focus of the safety study involving Eteplirsen in patients with DMD mentioned in the content?

A

Exon 51 skipping compound

70
Q

Describe the aim of Gentamicin in the clinical trial context provided in the content.

A

Stop mutation read through

71
Q

What is the purpose of GSK2402968 in the clinical trial related to skeletal muscle regeneration?

A

Exon 51 skipping

72
Q

Define the goal of PRO044 in the context of the clinical trial mentioned in the content.

A

Exon 44 skipping

73
Q

How is Revatio (SRP-4053) expected to impact patients with DMD in the clinical trial described in the content?

A

Exon 53 skipping

74
Q

Do you know the primary objective of Drisapersen in the clinical trials discussed in the content?

A

Restore dystrophin function by inducing exon skipping

75
Q

Describe the suggested reading materials related to Duchenne muscularrophy.

A

The suggested reading various articles and chapters covering topics such as muscle knowledge, animal models, new therapies, gene therapy, stem cell-based therapies, genetic treatments, aminoglycoside antibiotics, and exon-skipping therapy for Duchenne muscular dystrophy.

Investigation Of Human Disease (19 decks)

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