Page last updated 21st January 2025

For information on symptoms and support, see our SMARD1 pages >.

There have been two expert workshops by the ENMC (European Neuromuscular Centre) on SMARD1. The last onetook place in 2012 and provided a clinical and scientific update on the condition¹.

Models for SMARD1 Research

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.

A mouse model for SMARD1 has been available since 1995 that has a mutation within the IGHMBP2 gene. Known as the nmd2J model, these mice have early-onset weakness in the hind legs and other difficulties that mimic human SMARD². Different muscles in the nmd2J mice display different vulnerability to disease, but – unlike in SMARD1 – the diaphragm muscle is relatively unaffected³.

More recently, several new mouse models for SMARD1 research have been created, some of which have mutations in IGHMBP2 that mimic mutations found in the human condition^4-6. Importantly, some of these mice better reflect the human condition, e.g., their diaphragm muscle is clearly affected. These mice therefore provide a powerful new set of models for researching SMARD1 that will be of great use in improving understanding of the condition and developing potential therapies.

In addition to mice, SMARD1 has also been modelled using human neurons produced from skin samples taken from people with the condition^7-8. These human neurons have the same genetic mutations as the skin sample donors, which allows researchers to study the function of IGHMBP2. So far, the SMARD1 neurons have been shown to have growth and structural problems, which have been corrected upon different potential treatments. In combination with mice, the human neuron models will be essential for the development and testing of potential SMARD1 treatments.

Gene Therapy

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 mice^3,4.

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 neurons⁹. 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 mice¹⁰. Furthermore, this work also showed that the virus was capable of improving the health of human motor neurons derived from patients.

In follow-up work from the Lorson Laboratory, different routes of gene therapy administration were also tested¹¹. Delivery of gene therapy directly to the brain or into the blood were both shown to improved survival of SMARD1 mice; however, only those receiving injections into the brain showed improvements in function of their leg muscles.

In a further publication, SMARD1 mice received the gene therapy at different stages of disease (from 2 days old to 8 days old)¹²; treatment at all ages resulted in improvement in disease symptoms, but those receiving the earliest treatment showed the best outcomes. Therefore, similar to 5q SMA, it is likely that the earlier that SMARD1 is treated, the better the outcome will be.

Together, these pre-clinical studies demonstrated the feasibility of using viral gene therapy to treat SMARD1 and resulted in a phase 1 clinical trial of the treatment being initiated in late 2021¹³. Enrolment of participants continues (as of early 2025) and is by invitation only. 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.