Genetic SRT May Be Promising Treatment for Sanfilippo Syndrome, Similar Disorders, Review Finds

Genetic substrate reduction therapy (gSRT) may become a promising new avenue to treat patients with lysosomal storage disorders such as Sanfilippo syndrome, according to a review study.

The review, “Genetic Substrate Reduction Therapy: A Promising Approach for Lysosomal Storage Disorders,” published in Diseases, focused on gathering, summarizing, and discussing the benefits and challenges of multiple types of RNA-degrading technologies designed to achieve genetic SRT.

Lysosomal storage disorders (LSDs) are a group of rare genetic disorders characterized by the excessive accumulation of substances inside lysosomes (small cell compartments that digest and recycle several molecules), and are typically caused by a genetic mutation that leads to the activity of special enzymes responsible for breaking down these substances.

Some storage disorders, including Sanfilippo syndrome (also known as MPS III), Gaucher disease, Fabry disease and Batten disease, are also neurodegenerative conditions associated with the progressive loss of patients’ cognitive abilities.

Although conventional enzyme replacement therapy (ERT), in which a faulty enzyme is replaced by a healthy one to facilitate the elimination of substances accumulated inside lysosomes, seems to be highly successful for some of these disorders, it fails to address the neurological impairments associated with these conditions.

So, the need to develop novel alternative therapies that might overcome this limitation became a top priority for researchers and physicians alike.

Unlike enzyme replacement therapy, substrate reduction therapy (SRT) from the start prevents the body from producing and accumulating these toxic deposits inside cells.

While it does not completely shut down the production of these substances (substrates), it lowers their levels substantially, to the point where the patients’ own enzymes are enough to maintain a healthy equilibrium.

Substrate reduction therapy-based treatments are already approved in the U.S. and Europe to treat other lysosomal storage disorders, such as Zavesca (miglustat) and Cerdelga (eliglustat), which are indicated for Gaucher disease type 1 and Niemann-Pick type C disease.

In this review, researchers focused on a specific subtype of SRT, called genetic SRT (gSRT), which is based on the use of RNA-degrading technologies, such as RNA interference (RNAi) and single strand antisense oligonucleotides (AOs), intended to genetically reduce the production of substrate substances inside cells.

RNAi technology silences the activity of a gene of choice by taking advantage of the cells’ own natural machinery to prevent target messenger RNA (mRNA) molecules from being translated into proteins.

So far, RNAi has been successfully used to achieve genetic SRT by reducing the production and accumulation of glucosylceramide and glycosaminoglycans in cell lines genetically modified to produce higher levels of the substrate — or in patient-derived cell lines of Gaucher disease and in two forms of Sanfilippo syndrome, MPS IIIA for the accumulation of glucosylceramide and MPS IIIC for glycosaminoglycans.

AOs are another type of gene silencing tool based on the use of single strand molecules that are complementary to the target mRNA molecules that are to be silenced. This technology has been successfully used to achieve gSRT by decreasing the levels of glycogen in a mouse model of Pompe disease.

These findings demonstrate that the therapeutic potential of RNA-degrading technologies is promising, since genetic SRT could be achieved in every technique and could be applied to several lysosomal storage disorders.

“An additional advantage of gSRT approaches is the fact that they hold the potential to act at a neurological level since the RNA-degrading effectors are small molecules capable of crossing the [blood brain barrier],” researchers wrote. “Still, translation into clinics requires proper vectors for in vivo deliverance and suitable animal models to test the approach before trials.”

“This kind of approach would likely allow for the creation of multifunctional mixtures, as different diseases share the same accumulating substrates,” they added.

“Therefore, instead of a ‘one-compound-to-one-disease’ approach, gSRT (as SRT in general) may pave the way for a ‘one-compound-to-treat-several-diseases’ era, reducing therapy costs and increasing the number of patients with available therapeutic options.”