BURLINGTON, Mass. & BEIJING– CANbridge Pharmaceuticals Inc. (HKEX:1228), a leading China-based global biopharmaceutical company committed to the research, development and commercialization of transformative rare disease and rare oncology therapies, announced that data on a novel second-generation spinal muscular atrophy (SMA) gene therapy (CAN203), developed under the CANbridge and UMass Chan Medical School research agreement, was presented as a poster at the American Society of Gene and Cell Therapy (ASGCT) 26th Annual Meeting, in Los Angeles.
In a study entitled “Low-dose intracerebroventricular delivery of a second-generation AAV gene therapy for spinal muscular atrophy achieves efficient and toxicity-free motor function rescue in mice,” researchers reported that a novel second-generation hSMN1-AAV gene therapy vector, consisting of an endogenous SMN1 promoter and codon-optimized human SMN1 transgene, improved life span and motor function in a mouse model of SMA better than the benchmark vector, when delivered via intracerebroventricular (ICV) injection. The benchmark vector is identical in design to the only approved gene therapy for SMA. Furthermore, the second-generation gene therapy resulted in higher levels of SMN protein in the central nervous system (CNS), particularly within motor neurons, and lower expression in the peripheral tissues, compared to benchmark vector-treated mice.
Specifically, researchers compared the second-generation vector construct, packaged into two different capsids, against the benchmark vector by ICV injection at two doses, high (3.3×1013 vg/kg) and low (1.1×1013 vg/kg). These doses were one-tenth of those evaluated in an earlier intravenous (IV) study. At the high dose, the second-generation and benchmark vector-treated cohorts had 100% survival at the end of the 90-day study period, while at the low dose, both second-generation vector-treated cohorts had better survival than the benchmark vector-treated group. Mice treated with second-generation vector, regardless of dose, also saw a faster improvement in the righting reflex, reaching response times comparable to those of the healthy carrier cohort by day nine, compared to day 11 for the benchmark-treated mice. At the high-dose, second-generation vector-treated mice achieved significantly better (p=0.043) rotarod performance after 90 days and both doses of the second-generation vector led to faster improvement in the grid test, compared to benchmark-treated mice. Importantly, the second-generation gene therapy increased SMN expression in the targeted tissues, specifically the CNS, and reduced off-target expression, better than the benchmark therapy, revealing expression patterns that more closely resembled those of healthy carriers. Superior transgene expression was observed in disease-vulnerable cells, including ChAT-positive motor neurons in the spinal cord.
In addition, because dorsal root ganglia (DRG) toxicity has been associated with AAV gene therapies, the researchers evaluated the transgene expression in the DRG of SMA mice. No evidence of DRG toxicity associated with superior SMN expression was observed at 90 days after ICV injection with the high dose of the second-generation gene therapy. In a separate study, researchers observed that a very high ICV dose (1.1×1014 vg/kg) of the second-generation gene therapy in healthy mice maintained superior SMN protein expression after one year, compared to the same dose of the benchmark therapy, suggesting durability of treatment. The researchers also did not observe any signs of DRG toxicity associated with prolonged and superior SMN expression, as indicated by a normal clasping response and DRG morphology.
“Intravenous delivery of gene therapy has been successfully used to treat infants with SMA type 1, but it will be challenging to treat older patients who need much more viral vector or have pre-existing anti-AAV antibodies,” said Jun Xie, PhD, associate professor of microbiology & physiological systems, UMass Chan Medical School, and lead study author. “Direct CNS delivery of our second-generation hSMN1-AAV vector could enable gene therapy treatment for more SMA patients.”
“ICV delivery of CAN203 in the animal model results in a more targeted SMN expression profile using a low vector dose, which could lead to a safer and more efficacious gene therapy, with the potential to be used across all ages of patients with SMA when delivered directly to the CNS,” said Jason West, PhD, vice president, head of gene therapy research, CANbridge Pharmaceuticals. “We are pleased to advance CAN203 from these proof-of-concept nonclinical studies to IND-enabling studies.”
