Combining Spinraza with low-dose panobinostat — the active substance in an approved treatment for a blood cancer — may amplify Spinraza’s effectiveness, increasing the production of the survival motor neuron (SMN) protein whose lack is the underlying cause of spinal muscular atrophy (SMA), an early study in cell models found.

The study, “ Combined treatment with the histone deacetylase inhibitor LBH589 and a splice-switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells, ” was published in the Journal of Neurochemistry.

Most SMA patients have mutations in the SMN1 gene, which encodes for the survival motor neuron (SMN) protein: an essential protein to maintain the health of motor neurons necessary for muscle strength. These mutations render cells unable to produce sufficient amounts of SMN, leading to the death of motor neurons and the characteristic signs and symptoms of SMA.

People have an additional gene that can also make SMN, called SMN2. However, due to a process called splicing (which allows the same gene to give rise to different proteins), this gene mostly yields a shorter version of SMN that is quickly destroyed by cells.

The first targeted therapy approved for SMA, Spinraza (nusinersen, by Biogen), consists of an antisense oligonucleotide (ASO) that works to boost the body’s ability to produce SMN.

Spinraza works by increasing the ability of the SMN2 gene to produce a full-length, functional SMN protein. It does so by binding to the SMN2 messenger RNA or mRNA, which is a ‘blueprint’ of the SMN2 gene that the cell’s protein-making machinery ‘reads’ to produce the protein.

Although the medicine improves both motor function and survival of SMA patients, not everyone responds to this therapy with the same level of effectiveness. And as a recently approved therapy — in 2016 in the U.S. and 2017 in Europe — the long‐term tolerability and safety of Spinraza are not yet known.

Researchers explored if a combination approach, adding another therapeutic agent to Spinraza, might improve its benefits.

They focused on a class of agents called histone deacetylase (HDAC) inhibitors, which have been shown to enhance the ability of the SMN2 gene to produce a working SMN protein.

As many of these compounds have few side effects and are approved by the U.S. Food and Drug Administration as cancer therapies, researchers deem them as “excellent candidates” to repurpose for other diseases, including SMA.

Previously, two HDAC inhibitors — phenyl butyric acid (PBA) and valproic acid (VPA) — were tested in clinical trials for SMA, but little clinical benefit was seen.

In an attempt to discover more promising HDAC inhibitors, researchers preformed early screenings on skin cells derived from SMA type 1 patients, where the potency of four of these agents — TSA, LBH589, SAHA, and VPA — were compared side by side.

The most effective candidate — the best at correcting SMN2 splicing defects and rescuing the production of a working SMN protein — was LBH589, also known as panobinostat. This agent is the active substance in a treatment for multiple myeloma (a type of blood cancer), sold under the brand Farydak, by Secura Bio.

LBH589’s ability to restore a functional SMN protein was further confirmed in another cell model of SMA — stem cells that give rise to neurons (NSCs, neuronal stem cells) — derived from SMA type 1 mice. This particular experiment also suggested that a low dose of LBH589 was enough to raise the levels of full-length SMN in neuronal cells.

Importantly, researchers evaluated if LBH589 together with Spinraza could enhance its efficacy. The team treated SMA cells with sub-optimal doses of LBH589 and an oligonucleotide identical to Spinraza, and saw that combining these two compounds amplified SMN production.

Researchers believe that LBH589 acts by opening the three-dimensional structure of the SMN2 gene, favoring its activation and making its associated mRNA more accessible to be targeted by Spinraza.

“These findings suggest that HDAC inhibitors can potentiate the activity of [Spinraza] and support the notion that ‘SMN‐plus’ combinatorial therapeutic approaches might represent an enhanced opportunity in the scenario of SMA therapy,” the researchers wrote.

Future studies may explore LBH589 efficacy when combined with Spinraza and other SMA treatments, the researchers noted, such as the gene therapy Zolgensma (approved earlier year) and risdiplam, an investigational therapy under development by Roche and Genentech.