Muscular Dystrophy (Dr. Young)

What is DMD

Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness due to the absence of dystrophin, a protein that helps keep muscle cells intact.

What pattern of inheritance is related to DMD

Duchenne Muscular Dystrophy follows an X-linked recessive inheritance pattern, primarily affecting males while females can be carriers.

X-linked inheritance pattern, chromosome Xp21

What are the symptoms of DMD

• Progressive skeletal muscle degeneration and weakness

• Cognitive impairment/mental retardation (not always)

• Low bone density

• Scoliosis of the spine

• Cardiomyopathy

• Fibrosis & fat accumulation in muscle tissue

Boys present early (before school age) with difficulty standing – need to use Gower’s manoeuvre to stand

• Wheelchair-bound by late teens, life expectancy late twenties

• Positive pressure ventilation employed to replace loss of diaphragm function

• Death is usually due to cardiomyopathy or diaphragm failure

What are the 7 isoforms of DMD

• Dp427M – Found in muscle (main full-length form).

• Dp427B – Found in cortical neurons (brain).

• Dp427P – Found in Purkinje cells (part of the brain).

• Dp260 – Found in the retina (important for vision).

• Dp140 – Found in the brain and kidneys (involved in cognitive function).

• Dp116 – Found in Schwann cells (supports nerve cells).

• Dp71 – Found in many tissues (especially in the brain and other non-muscle areas).

What is BMD

Becker Muscular Dystrophy is a milder form of muscular dystrophy caused by mutations in the dystrophin gene, characterized by progressive muscle weakness and wasting, typically with symptoms appearing in adolescence or early adulthood.

What is Nonsense-mediated decay (NMD) machinery

The process by which cells identify and degrade mRNA molecules that contain premature stop codons, preventing the production of truncated proteins that could be detrimental to the cell.

Stem cell

A type of undifferentiated cell capable of giving rise to various cell types in the body, often used in regenerative medicine and research.

What is the other name for muscle stem cells

Satellite cells

what are the cell based therapies for DMD

Gene therapy

Exon Skipping

Viral vectors

Ribosomal readthrough

What is the function of gene therapy to help DMD patients

• Gene Therapy:

  • The function of gene therapy for DMD patients is to replace or repair the defective dystrophin gene, enhancing muscle function and slowing disease progression.

  • Goal: Deliver a healthy copy of the DMD gene to muscle cells to produce dystrophin.

  • How it works: Uses a carrier (like a virus) to deliver the new gene and help restore some dystrophin production.

How do ribosomal read-through drugs help fight DMD

• Ribosomal Readthrough:

  • Goal: Help the cell ignore a stop signal caused by certain mutations, allowing it to finish making dystrophin.

  • How it works: Drugs (like ataluren) trick the cell’s machinery into reading past the mutation and continuing protein production.

What are the issues with viral vectors

1. the size; is limited to 8-10kb, need about 14kb for the DMD gene so it’s too big to be packaged, therefore ‘mini-dystrophins’ must be used. Are these fully functional?

2. problem is which promoter to use? These will be specific to muscle types and may not be active enough in a fully differentiated tissue. Viral promoters may cause other problems – may infect and induce expression in non-muscle cells!