Fundamental research

First step

Fundamental research, also called basic research,
takes place in the laboratory and is the first step
to developing treatments for SMA.

Intro

Investigating the cause & biology of SMA

Fundamental research projects investigate the cause and biology of SMA to better understand the disease and help to identify the most effective strategies for drug discovery.

For example, it was through fundamental research that it was discovered that SMA is caused by mutations in the survival motor neuron 1 gene (SMN1)¹. It has led to an improved understanding of the role of the survival motor neuron (SMN) protein and has also helped identify potential ways of manipulating the ‘back-up’ SMN2 gene to treat the condition.

See “What is SMA” for more information on the condition and how it is caused and the graphic below, Chromosome 5, showing the SMN1 and SMN2 genes.

In focus

New therapies for SMA

To continue to develop new therapies for SMA, it is vital that we improve our understanding of why motor nerves die and how other systems, pathways, and processes are involved.

The more we know about how SMA affects the human body, the more genes/ proteins we can potentially target to reduce symptoms. Through our Call for Research Proposals, we seek to fund projects that shed light on those mechanisms.

Without fundamental research, the SMA drug pipeline would not continue to grow and diversify. We need both a breadth and a depth of options in our quest for effective SMA treatments.

Questions

Some of the questions that remain²

What is the entire spectrum of tissues and networks affected in SMA?

How much SMN is needed, spatially and temporally, for normal functioning?

What are the novel emerging phenotypes arising from long-term treatment?

What is/are the main cellular mechanism(s) causing SMA?

What is the benefit of each SMN-dependent medicine compared with each other?

Is it meaningful to combine the different SMN-dependent therapeutics to achieve greater augmentation of SMN levels, especially in the first months of life and to target as many cells as possible?

What are the long-term effects of each of the therapies?

Will CNS-treated SMAType 1 patients develop multi-organ symptoms later in life? Is it necessary to start therapy prenatally in individuals with only two SMN2 copies?

When is a therapy too late or inefficient and should be stopped?

How can responders and non-responders be identified prior to treatment?

Can too much SMN as delivered by SMN-scAAV9 under the strong CMV enhancer/β-actin promotor become detrimental in older patients when only a little SMN is needed?

Would a different scAAV9 vector than the one used currently – for instance, with SMN expression under the endogenous SMN promotor – be a better choice?

When is the blood–brain barrier closed for scAAV9-SMN penetration in humans?

References

¹Lefebvre S et al. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80: 155-165.

²Wirth B. (2021) Spinal Muscular Atrophy: In the Challenge Lies a Solution. Trends Neurosci 44(4):306-322.