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Page last updated 28th November 2022

For information on symptoms and support, see our SMARD pages.

There have been two expert workshops by the ENMC (European Neuromuscular Centre) on SMARD. The last one took place in 2012 and provided a clinical and scientific update on the condition¹.

The way scientists and doctors develop treatments can be described as ‘translational medicine’; so called because it is translating scientific results into a treatment that can be given to individuals with a condition. One of the first steps along this pathway is developing ‘models’ to test treatments or to use in experiments to understand more about a condition. Such models may be cells from someone with the condition, or an animal (such as a mouse) that has a form of the condition – often resulting from a mutation in the same mouse gene that causes the human disease. There have been developments in this area for SMARD, with a mouse that has a mutation within the IGHMBP2 gene. These mice have early-onset weakness in the hind legs and other difficulties that mimic human SMARD². However, like many mouse models of disease it is not perfect. Nevertheless, this SMARD mouse has been used to develop a pre-clinical gene therapy to deliver a functional IGHMBP2 gene to parts of the body it is most needed.

Gene therapy is a technology that has been discussed many times in relation to the treatment of inherited conditions. The concept is that you use a virus to insert a working copy of the non-working gene into cells within the body – just like how Zolgensma works for 5q SMA. The body would then start using this and producing the protein that it was previously unable to make.

Two research groups have independently adapted this therapeutic strategy for SMARD and tested IGHMBP2-producing viruses on SMARD model mice3,4.

The laboratory of Christian Lorson showed that injection of the IGHMBP2 gene therapy into the brains of mice boosted the amount of IGHMBP2 protein in the brain, spinal cord, and, importantly, in the motor neurons3. Low and high doses of the virus were tested and, as expected, the increase in IGHMBP2 was shown to be dependent on the amount of virus injected.

The low dose increased survival of the SMARD mice from a median of 151 days to approximately a year. The increase in IGHMBP2 also improved motor neuron and muscle health, causing advances in weight gain and overall muscle strength in the mice. Less expected was the finding that the higher viral dose did not have a greater impact on disease progression. In fact, the opposite was observed; the high viral dose reduced SMARD mouse survival, and this was also shown when viruses were injected into the blood instead of the brain. It remains unclear why exactly this happened.

This highlights a very important feature of gene therapies – a larger increase in a protein does not always equate to greater improvements in symptoms. The concentration of a gene therapy dose must therefore be carefully considered and tested in pre-clinical experiments before moving to a clinical setting.

A second study from researchers at the University of Milan showed that injection of IGHMBP2-producing viruses into the blood stream rather than the brain had a similar positive effect on SMARD mice4. Furthermore, this work also showed that the virus was capable of improving the health of patient-derived motor neurons in culture.

Together, these pre-clinical studies demonstrated the feasibility of using viral gene therapy to treat SMARD and resulted in a phase 1 clinical trial of the treatment being initiated in late 20215. Six to ten people with IGHMBP2 mutations are expected to be enrolled in the trial, which will assess the safety of gene therapy injections into the fluid that bathes the brain and spinal cord.

1. van der Pol et al. (2013) 190th ENMC international workshop: Spinal muscular atrophy with respiratory distress / distal spinal muscular atrophy type 1: 11–13 May 2012, Naarden, The Netherlands. Neuromuscul Disord 23: 602-609.

2. Cook et al. (1995) Neuromuscular degeneration (nmd): a mutation on mouse Chromosome 19 that causes motor neuron degeneration. Mamm Genome 6: 187-191.

3. Shababi et al. (2016) Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent. Mol Ther 24: 855-866.

4. Nizzardo et al. (2015) Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model. Sci Adv 1: e1500078.