Lysogene Becomes Latest Company to Fail with AAVs in CNS Disorders (Updated)

Topline data from Lysogene’s Phase II/III AAVance study showed its investigational gene therapy, LYS-SAF302, failed to meet its primary and key secondary efficacy endpoints in mucopolysaccharidosis type IIIA.

In the study’s main cohort of 12 patients aged 30 months and above, treatment with LYS-SAF302 did not induce a statistically significant improvement in cognitive developmental quotient at 24 months. Lysogene’s candidate also had no significant impact on the percentage of patients stabilized or improved cognitive, language and motor developmental age.

However, when looking at a subset of patients younger than 30 months, LYS-SAF302 was associated with statistically superior cognitive development 24 months after dosing. In particular, treatment with the investigational gene therapy slowed the decline of the developmental quotient by 27% relative to age-matched natural history comparators, with a p-value of 0.037. 

A Lysogene told BioSpace that "there appears to be a point of no return beyond which loss of cognitive and behavioral function is irreversible."

"Once the disease progresses and a substantial number of neurons have died, it appears not be possible to rescue function," the spokesperson added.

Lysogene intends to capitalize on its findings that LYS-SAF302 could be promising in younger MPS-IIA patients and has held talks with regulatory authorities in the European Union to chart a way forward for the therapy. The company will extend these discussions to other regulatory bodies.

To support the continued development of LYS-SAF302, Lysogene is also working on securing more funds through a licensing collaboration for at least one of its programs.

The AAV Dilemma 

LYS-SAF302 works by delivering a functional copy of the human SGSH gene, which is typically defective in patients with MPS IIA. The biologic injects the gene directly into brain cells using an adeno-associated virus (AAV) vector, which had been modified to be particularly selective for cells in the central nervous system.

However, whether or not AAV approaches are viable for disorders of the central nervous system remains a point of contention, with many companies failing to get their candidates through the rigors of clinical trials.

In January, for instance, Amicus dumped its gene therapy program for CLN6 Batten disease after finding that the initial promising findings were not robust in the long run. The company’s candidates for this indication were AAV-based.

In a 2021 review, researchers from China and the U.S. outlined key barriers to using AAV-delivered gene therapies in neurological diseases. These include toxicities due to off-target expression of AAV’s gene payloads, the body’s immune response against the AAV carriers and the near-impenetrable blood-brain barrier.

The Lysogene spokesperson added that "many CNS diseases are neurodegenerative in nature." Because neurons cannot regenerate, treatments that hope to target CNS conditions "must be initiated before massive neuronal damage has occurred."

This poses a challenge for many companies which will have to deal with the challenge of determining "the time window of effective intervention." 

Still, some companies have seen success with AAV, enough to keep it a prominent approach in neuro diseases. In June, uniQure’s AAV-based gene therapy achieved promising results in Huntington’s disease, cutting the level of mutated huntingtin protein in the cerebrospinal fluid by more than half. Earlier this month, a Data Safety Monitoring Board gave the company the green light to continue its high-dose gene therapy trial in Europe.