Geijsen Group – Tackling Inherited Genetic Muscle Diseases using Genome Editing, Protein Engineering and Models of Embryonic

Gastrulation

Many congenital diseases have their origins in early embryonic development. Gastrulation is a particularly critical event that occurs shortly after implantation, when the different embryonic germ layers are specified and the 3D body plan of the embryo is laid out. However, we know almost nothing about these processes during early human development.

Pluripotent stem cells can self-organize to form 3D structures resembling gastrulation stage embryos. These ‘gastruloids’ form the 3 germ layers, as well as the body axes, recapitulating many of the spatial cues and 3D organization of the early developing embryo.

• Gastruloids display axial elongation and form somites containing muscle progenitors and we are using murine and human gastruloids to study early muscle development.

Knowledge of this will shed light on normal and abnormal development of skeletal muscle and shed light on the mechanisms underlying skeletal muscle disorders.

Genetic muscle disorders

Skeletal muscle comprises more than 40% of our body weight and is essential for support, physical movement, protection of internal organs, breathing and metabolism. Muscular dystrophies are genetically inherited diseases characterized by progressive wasting of muscle. We aim to utilize our knowledge and findings to tackle muscular dystrophies.

We focus on two genetic muscle disorders:

Duchenne Muscular Dystrophy (DMD)

Is a devastating muscle wasting disease caused by out-of-frame mutations in the DMD gene, which occurs in 1:5.000 male births. DMD codes for dystrophin, a protein that supports muscle fiber strength, and loss of dystrophin expression causes membrane instability of the muscle fibers. As a result, muscle tissue is lost and patients become wheelchair dependent, lose the ability to use their hands and arms and ultimately die due to respiratory or cardiac failure in their early to mid-twenties.

Facioscapulohumeral muscular dystrophy (FSHD)

Is an autosomal dominant gain of function disease, often affecting young adults before they are 20 years of age. FSHD affects mainly the upper body, including the face, shoulder blades and arms. Although the molecular pathophysiology of FSHD is complex and not well understood, abnormal activation of the DUX4 gene is a causative factor triggering muscle fiber decay in these patients.

Expanding the CRISPR/Cas toolbox

There’s no doubt that the development of CRISPR/Cas, an immune surveillance system in bacteria and archaea, into a precise genome editing tool is one of the most significant scientific discoveries of this century. CRISPR/Cas is flexible, easy-to-use, fast and incredibly efficient. New, CRISPR-based effector technologies are rapidly expanding the versatility of our genome editing toolbox.

• Using genetic muscle disorders as disease model systems, we’re developing new gene editing technologies with the hope that they can one day contribute in the treatment of these disorders.

We aim to expand the CRISPR/Cas toolbox by developing new Gene editing variants, targeting methods and delivery technologies