Spinal muscular atrophy (SMA) – research from gene and modifiers to therapy

The fascinating research of Professor Brunhilde Wirth is placed under the spotlight, concerning her work in the field of disease-causing genes, modifier pathways and pathomechanisms of neuromuscular disorders, focussing on spinal muscular atrophy (SMA)

Professor Brunhilde Wirth focuses her research on the identification and understanding of disease-causing genes, modifier pathways and pathomechanisms of neuromuscular disorders, mainly of spinal muscular atrophy (SMA) and further motor neuron disorders.

More recently, she has extended her research activities also on osteoporosis and the understanding of bone development and remodelling. In order to identify the genetic cause of the disease, the group applies the most advanced technologies including next-generation sequencing and transcriptome analysis. The laboratory has been developing and is using a large number of different methods and technologies to understand the genetic, biochemical, cellular and pathological basis of motor neuron disorders and osteoporosis. They are generating and using conditional and transgenic motor neuron mouse models, zebrafish and most recently, Drosophila models as well as induced pluripotent stem cells. Their utmost goal is the development of therapies, which is a particularly strong interest of the group.

As the Wirth lab has now contributed major research findings for over 25 years, this has enhanced our understanding of:

  • The genetic basis of SMA including deletions, rare point mutations or gene conversion events;
  • The mechanism for the unusual alternative splicing of the copy gene SMN2 that differs from the full functional SMN1 copy by a single silent base exchange;
  • The correlation of SMN2 gene copies with the severity of the disease. Each individual with SMA has no SMN1 but one-to-six SMN2 copies. The SMA severity inversely correlates with the copy number of SMN2 genes. SMN2 produces only low levels of correct SMN protein which is unable to maintain the function of motor neurons, the mainly affected cell system causing SMA;
  • Genetic modifiers, such as increased levels of plastin 3 (PLS3) or decreased levels of neurocalcin delta (NCALD) or calcineurin like EF-hand protein 1 (CHP1) protect against SMA;
  • Modifiers act protectively in SMA mouse and zebrafish models;
  • The major cellular disturbed pathway in SMA is an impaired endocytosis;
  • Therapies using SMN-dependent (such as the HDAC inhibitor, valproic acid or antisense-oligonucleotides (ASOs) such as SPINRAZA and SMN-independent approaches (ASOs against genetic modifiers, NCALD and CHP1).

The Wirth lab is aware that for future therapeutic development patenting the intellectual property is essential: their findings to SMA genetic modifiers have therefore been patented.

Prof Wirth believes that once SMA is included in neonatal screening, individuals with SMN1 deletions can be treated pre-symptomatically with SMN-dependent and SMN-independent ASOs, small molecules or gene therapy approaches, which most likely will allow curing SMA. There is still some way to go until reaching this final goal.

Please note: this is a commercial profile

 

spinal muscular atrophy

Brunhilde Wirth

Chair of the Institute of Human Genetics

University Hospital of Cologne

University Cologne

Tel: +48 221 478 86464

brunhile.wirth@uk-koeln.de

http://humangenetik.uk-koeln.de/

www.twitter.com/BrunhildeWirth

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