Antisense oligonucleotide (ASO) therapies have recently shown success in neurological diseases. One ASO therapy, which selectively targets the disease-causing gene, has been approved for Alexander disease, a rare disorder impairing neurodevelopment. Several companies are now working on ASO therapies for Phelan-McDermid syndrome (PMS).
What are ASOs, and how were they originally used?
ASOs, or antisense oligonucleotides, are short strings of genetic code that selectively target genes to modulate protein production. Inside each cell, the genetic DNA code is read and transcribed into RNA, a different flavor of genetic code that cells can use directly to produce the corresponding protein. The amount of RNA directly influences how much protein is made. ASOs bind selectively to RNA, guided by its distinct, gene-specific sequence. Originally, ASOs were used to destroy RNA, because the cell flags ASO-RNA complexes as garbage. In Alexander disease, this approach greatly reduces production of the disease-causing protein in brain cells.
Evolving applications of ASOs: tuning genes up
However, ASOs are versatile and can also be used to increase protein production. For spinal muscular atrophy (SMA), an approved ASO therapy (Spinraza) was developed as a splice modulator that rearranges RNA composition to make more lifesaving SMN protein available to nerve cells. Recently, an ASO designed to upregulate SYNGAP1 protein production was cleared for clinical trials. This is directly relevant to Phelan-McDermid syndrome, since SYNGAP1-related disorder is caused by a 50% reduction in SYNGAP1 protein, just as PMS is caused by a 50% reduction in SHANK3 protein.
How are ASOs administered to people with neurological disorders?
Currently, ASOs must be injected into the spinal canal, often under anesthesia, so that the cerebrospinal fluid (CSF) can carry them into the brain. They must be re-dosed about three times a year to maintain a robust effect. The dose can be adjusted to what is optimal for each patient, and ASOs clear completely from the body within weeks if treatment is stopped.
However, research into ASO administration is progressing rapidly. ASO is an umbrella term for an increasing variety of designs, with various chemical formulations and modifications that can increase stability and tolerability. Recent innovations aim to improve distribution in the brain by linking ASOs to lipids. In the future, ASOs may be able to cross the blood-brain barrier safely and efficiently, enabling at-home injections or even skin patches.
What ASO therapies are in development for PMS?
Several companies are currently developing ASOs for PMS, using complementary approaches. The furthest along is PYC Therapeutics, with an ASO targeting an RNA regulatory region that follows the SHANK3 gene information. Binding of this ASO to SHANK3 RNA increases the amount of SHANK3 protein, as demonstrated in multiple preclinical studies. PYC Therapeutics is currently completing the data package to apply to government health regulators for clinical trial authorization. CAMP4 Therapeutics recently announced a SHANK3 program in which ASOs are being designed to increase SHANK3 protein by upregulating SHANK3 RNA production, an approach different from that of PYC Therapeutics. Preclinical data will become available at a later date.
Further concepts and approaches for using ASOs as PMS therapy are being pursued by academic, biotech, and biopharma researchers. We look forward to hearing more about these programs as they mature.
Not all ASO therapies are expected to succeed in the clinic – recently clinical development of one of the three ASO therapies for Angelman syndrome, another neurodevelopmental disorder, was stopped while the other two ASO therapies for Angelman are pressing ahead in late-stage clinical trials.
CureSHANK is at the forefront of PMS research and treatment development. We will continue to keep our community informed as ASO therapy clinical trials are updated or initiated.
Ralf Schmid is the Chief Scientific Officer (CSO) at CureSHANK and can be reached at research@cureshank.org
