New approach may help Spinraza treatment to cross BBB

Researchers have designed a way to help therapies like Spinraza (nusinersen) — approved for spinal muscular atrophy (SMA) — better access the brain and spinal cord when delivered into the bloodstream.

In a recent report, the scientists linked a molecule similar to Spinraza with small protein fragments capable of crossing the selective blood-brain barrier (BBB) that normally prevents substances in circulation from getting into those tissues. When delivered into the bloodstream of mice, it could get into the brain and act as intended.

Researchers touted the findings as “a significant step towards developing systemically administered neurotherapeutics for a range of … disorders” that could eventually eliminate the need for more invasive routes of delivery that are currently used.

The study, “Efficient systemic CNS delivery of a therapeutic antisense oligonucleotide with a blood-brain barrier-penetrating ApoE-derived peptide,” was published in Biomedicine & Pharmacotherapy.

Antisense oligonucleotide (ASO) therapies are gaining ground as an approach for diseases like SMA. These small strands of genetic material — DNA or RNA — bind to specific sections of a gene to modify its activity and alter protein production.

Spinraza is antisense oligonucletide therapy approved for SMA

Spinraza is an ASO that’s approved for SMA. In the disease, mutations in the SMN1 gene mean that not enough of the SMN protein is produced. There’s a backup SMN producer, SMN2, but it isn’t nearly as effective at making SMN protein.

That’s because the gene produces some versions of SMN2 mRNA — a template for protein production — that don’t yield the normal, full-length SMN protein that SMN1 makes. Spinraza is designed to essentially increase SMN2’s production of the full-length SMN2 mRNA transcript, thereby boosting SMN levels.

A caveat to ASOs is that they don’t readily cross over the selective BBB that protects the central nervous system (CNS) — the brain and spinal cord — from potentially harmful substances in circulation. With minimal access to those tissues when delivered systemically, the therapeutic potential of ASO-based therapies for neurological diseases is limited.

That’s why Spinraza is given as an injection directly into the spinal canal, called an intrathecal injection. This places the medication directly into the fluid that circulates in the CNS and bypasses the BBB. However, this mode of administration comes with its own limitations, with possible side effects like headache, back pain, and bacterial infections.

It’s thus of interest to find ways of enabling ASO therapies like Spinraza to more easily cross the BBB when delivered into circulation.

In the study, researchers designed several BBB-penetrant protein fragments, or peptides, that could be fused to an ASO to help carry it across the BBB and into the CNS. The peptides were derived from proteins known to be able to cross over the selective barrier. They then linked the peptides to an ASO chemically comparable to Spinraza and looked at the effects when it was administered to cells from SMA patients in the lab.

Peptide-fused ASOs increased expression of full-length SMN2 transcripts

The peptide-fused ASOs significantly increased expression of full-length SMN2 transcripts in a concentration-dependent manner.

A few promising candidates were then administered directly into the bloodstream of mice genetically engineered to lack one copy of their SMN2 gene, with injections happening weekly for five weeks. These mice would be expected to have lower SMN2 activity, but do not show overt symptoms associated with it.

One candidate in particular was found to significantly increase expression of full-length SMN2 mRNA in the brain and spinal cord without causing toxicity. Importantly, the treatment did not lead to signs of liver toxicity or potentially harmful immune reactions.

Additional experiments showed the treatment was well distributed throughout the CNS. About 78% of it reached the brain, and around 11% of nerve cells took up the therapy.

Overall, the researchers believe their approach “could potentially offer a safer alternative to the current … approved ASO (Spinraza) which is administered through invasive intrathecal injection,” they wrote.

They added the approach will next need to be tested in SMA mouse models to see if the increase in full-length SMN2 eases disease-associated symptoms.