Chemically Modified Nucleic Acids in Medicine

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What was the mean change from baseline in the mNIS+7 score for patients receiving patisiran at 18 months?

28.0 points

18.0 points

-34.0 points

-6.0 points (correct)

What was the difference in the baseline Norfolk QOL-DN score between the patisiran and placebo groups?

3.5 points

2.8 points

6.1 points

4.1 points (correct)

How did the gait speed change from baseline in the patisiran group compared to the placebo group at 18 months?

0.08 m per second vs -0.24 m per second (correct)

0.31 m per second vs -0.31 m per second

-0.08 m per second vs 0.24 m per second

-0.24 m per second vs 0.08 m per second

What was the incidence of mild or moderate infusion-related reactions in the patisiran group?

20% Signup and view all the answers

What was the least-squares mean change in modified BMI for the placebo group at 18 months?

-119.4 Signup and view all the answers

What is the significance of the SMN protein level in relation to SMA severity?

SMN protein levels correlate with the severity of SMA. Signup and view all the answers

Which mutation in the TTR gene is most commonly associated with transthyretin amyloidosis?

Valine to methionine at amino acid 30 Signup and view all the answers

What is a characteristic of the transthyretin protein?

It is a 55kD tetramer with two thyroxine binding sites. Signup and view all the answers

What is the main treatment approach of Patisiran for transthyretin amyloidosis?

Triggering degradation of TTR mRNA. Signup and view all the answers

What is the duration of significant morbidity for most patients with hereditary ATTR amyloidosis?

2-15 years from symptom onset. Signup and view all the answers

What type of drug is Patisiran?

Double-stranded siRNA. Signup and view all the answers

Which condition can be a symptom of multisystem disease caused by transthyretin amyloidosis?

Heart failure. Signup and view all the answers

What happens to transthyretin tetramers in transthyretin amyloidosis?

They dissociate into miss-folded monomers that aggregate. Signup and view all the answers

What is the mode of inheritance for Spinal Muscular Atrophy?

Autosomal recessive Signup and view all the answers

What is the primary function of the SMN1 and SMN2 genes?

They encode the same protein. Signup and view all the answers

What significant issue does the SMN2 gene face that contributes to Spinal Muscular Atrophy?

It has a sequence that prevents the inclusion of Exon 7. Signup and view all the answers

How does nusinersen function in treating Spinal Muscular Atrophy?

It blocks negative splicing factors, enabling proper splicing. Signup and view all the answers

Which type of Spinal Muscular Atrophy is classified as severe with a life expectancy of less than 2 years?

Type I Signup and view all the answers

What percentage of the population are carriers of Spinal Muscular Atrophy?

1 in 50 Signup and view all the answers

What is the role of 2'-O-methyl (2'-OMe) in chemically modified oligonucleotides?

It prevents degradation of the oligonucleotide. Signup and view all the answers

Which statement correctly describes the function of phosphorodiamidate morpholino oligomers (PMOs)?

They have uncharged groups making them resistant to degradation. Signup and view all the answers

What significant event concerning SMA was discovered in 1995?

The identification of SMN1 deletions as the cause of SMA. Signup and view all the answers

In the context of Duchenne's Muscular Dystrophy (DMD), which characteristic is true?

Most patients are diagnosed between the ages of 3 and 5. Signup and view all the answers

Which of the following statements about the FDA's approval for SMA treatments is accurate?

FDA approved accelerants for commercial use. Signup and view all the answers

What is the primary function of microRNAs in the regulation of gene expression?

To bind to target mRNAs and block translation or trigger cleavage. Signup and view all the answers

Which of the following correctly describes the splicing of pre-mRNA?

A lariat-like intermediate is formed during the process. Signup and view all the answers

What characterizes shRNAs compared to microRNAs?

ShRNAs are more selective and have fewer targets. Signup and view all the answers

What occurs primarily within the nucleus with regard to human messenger RNAs?

They are processed through splicing to remove introns. Signup and view all the answers

Which of the following is NOT a step in miRNA biogenesis?

Export to ribosome. Signup and view all the answers

Which component is involved in the cleavage and degradation of target mRNA during RNA interference?

RISC. Signup and view all the answers

Which of the following describes the composition of myofibrils in striated muscle cells?

They are composed of both thin and thick filaments. Signup and view all the answers

In the context of the study on patisiran, what was the primary endpoint measured?

The change in modified Neuropathy Impairment Score+7 at 18 months. Signup and view all the answers

What is a key characteristic of shRNAs used as therapeutics?

They are specifically designed to degrade target mRNAs. Signup and view all the answers

Which condition is primarily affected by chemically modified oligonucleotides that influence splicing?

Spinal Muscular Atrophy Signup and view all the answers

What is the purpose of the Norfolk Quality of Life-Diabetic Neuropathy questionnaire in the patisiran trial?

To evaluate the quality of life related to diabetic neuropathy. Signup and view all the answers

What type of RNA does patisiran primarily target in its mechanism of action?

Specific target mRNAs related to transthyretin amyloidosis. Signup and view all the answers

How is the dosage of patisiran administered in the clinical trial?

Once every 3 weeks. Signup and view all the answers

Which components make up one sarcomere?

H-band, A-band, I-band, Z-line Signup and view all the answers

What is a significant characteristic of dystrophin?

It has a long central rod domain composed of spectrin repeats. Signup and view all the answers

What happens in Becker's Muscular Dystrophy?

Exon deletions result in shorter but functional dystrophin proteins. Signup and view all the answers

How does splicing occur at the molecular level?

It involves specific binding sites in pre-mRNA. Signup and view all the answers

What is a characteristic of Phosphorodiamidate Morpholino Oligomers (PMOs)?

They can inhibit RNA splicing by binding to RNA. Signup and view all the answers

What is the purpose of Exondys 51?

To skip exon 51 in dystrophin and restore reading frame. Signup and view all the answers

What was the outcome of the Phase I/II trial for Exondys 51?

Dystrophin levels were restored to 0.93% of normal. Signup and view all the answers

What impact does a mutant dystrophin have on muscle fibers?

It disrupts the mechanical link between the cytoskeleton and matrix. Signup and view all the answers

Study Notes

Chemically Modified Nucleic Acids as Therapeutics

Oligonucleotides modify pre-mRNA splicing, impacting diseases like Muscular Dystrophy (Sarepta) and Spinal Muscular Atrophy (Ionis and Biogen).
shRNAs induce target mRNA degradation, used in treating Transthyretin amyloidosis (Alnylam).

Chemical Modifications of DNA and RNA for Therapeutics

Modifications like phosphorothioate (PS) backbones, 2'-O-methoxyethyl (2'-MOE), and 2'-O-methyl (2'-OMe) substituents improve resistance to degradation and enhance protein binding to target RNA.
These modifications are crucial for therapeutic efficacy.

DNA-Phosphodiester Linkages

DNA's structure involves phosphodiester linkages connecting deoxyribose rings.
The major and minor grooves define DNA's structure.

Splicing Mechanism of mRNA

Splicing involves RNA-protein complexes and biochemical reactions.
This process removes introns from pre-mRNA and joins exons.

Duchenne Muscular Dystrophy (DMD)

DMD is the most common muscular dystrophy type, affecting 1 in 3300 boys.
It's an X-linked recessive disorder causing a dystrophin gene mutation.
DMD patients typically use wheelchairs by age 12 and often die in their 20s due to respiratory or heart failure.

Dystrophin Protein

Dystrophin is a large, complex protein.
It contains many "spectrin repeat" linkers and "hinge" regions crucial for function.
Dystrophin links the cytoskeleton to the extracellular matrix, providing structure and support.
Damage to the dystrophin-associated protein complex (DAPC) disrupts muscle fiber integrity, increasing vulnerability to damage.

Becker's Muscular Dystrophy

A less severe form of muscular dystrophy where some dystrophin protein is produced, resulting in less severe symptoms.
A17-48 (BMD mutation) retains the N-terminal and C-terminal domains crucial to maintaining functionality.
Mutations may affect splicing.

Molecular Approaches for DMD Therapy

Splicing is influenced by RNA protein complexes and specific sites.
Antisense oligonucleotides target pre-mRNA, preventing splicing or introducing modifications.

Exon Skipping Therapy (Exondys 51)

Exon skipping aims to eliminate problematic exons.
A silencing of a given exon is caused by the binding of a PMO which then prevents splicing of that exon.
Exondys 51 employs a morpholino oligonucleotide (PMO) to skip exon 51.
This method results in reduced but still functional dystrophin.

Exondys 51 Trial Results

Phase I/II trials showcased improvements, with significant restoration of normal dystrophin levels.
FDA approval was received, but the treatment is not approved in Europe.

Spinal Muscular Atrophy (SMA)

Caused by the loss of the SMN1 gene (autosomal recessive).
Severity varies depending on remaining SMN2 function.
Symptoms include muscular weakness, atrophy, and often fatal paralysis in early childhood.
Until recently, there were no effective treatments.

Antisense Oligonucleotides for SMA

Used to enhance correct (or improve) splicing of SMN2 mRNA in the nucleus.
SMN1 and SMN2 encode the same protein yet have minor differences which lead to a non functional mutant SMN protein during translation.
Targeting the intron 7 splice site is one method to improve the efficiency of translation.

Nucleic Acid Therapy for SMA (Nusinersen)

Aims to restore correct splicing of SMN2 mRNA.
Nusinersen (Spinraza) is a commercially available antisense oligonucleotide.
Targeting the intronic splicing silencer can improve Exon 7 inclusion in SMN2 mRNA, resulting in more functional SMN protein.

Transthyretin Amyloidosis

Transthyretin (TTR) is a protein involved in transporting thyroxine.
Mutations in the TTR gene can lead to misfolded TTR protein aggregation.
Amyloid fibrils are deposited in various organs, leading to multi-system disorder.
Mutations cause dissociation of tetramers into misfolded monomers that aggregate into amyloid fibrils.
Treatment includes interfering with the expression of TTR using short helical interfering RNAs.

Patisiran (Alnylam's Drug for Transthyretin Amyloidosis)

An siRNA drug formulated in lipid nanoparticles.
Delivered directly to liver cells (hepatocytes).
Targets TTR mRNA, leading to its degradation and reduced TTR synthesis.
The pyrimidines in the sense strand and uracil residues in the antisense strand are 2'-O-methyl modified ribonucleotides.
The internucleotide linkages are un-modified phosphodiester linkages.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

Explore the role of chemically modified nucleic acids as therapeutics in the treatment of diseases such as Muscular Dystrophy and Spinal Muscular Atrophy. Delve into the mechanisms of oligonucleotide splicing, the importance of chemical modifications, and the structure of DNA in therapeutic applications.