For these diseases, we design zinc finger transcriptional regulators (ZF-TRs) to modulate gene expression levels in the brain. We package these into AAV vectors designed specifically for nervous system delivery.
Our preclinical neurological targets include chronic neuropathic pain, prion disease, Huntington’s disease and ALS.
Neuropathic pain is one of the most difficult pain syndromes to manage. To address this challenge, we are developing zinc finger repressors targeting the SCN9A gene, which codes for the Nav1.7 protein. Our aim is to specifically target and reduce Nav1.7 expression in dorsal root ganglia to prevent nociceptive pain signals from reaching the brain. Lowering Nav1.7 is expected to reduce pain without adversely affecting other sensory functions.
In May 2023, we presented our first preclinical data for this program at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting. We showed that our engineered ZFRs potently repressed the SCN9A gene in cultured neurons, with exquisite specificity. In addition, we found that treatment of a mouse model of neuropathic pain with AAV-ZF-Rs led to significant repression of SCN9A in dorsal root ganglia and restored mechanical- and cold-induced pain responses to normal levels. ZFRs targeting SCN9A were also well tolerated in non-human primates, at all doses tested, with no adverse findings related to treatment. These results support the continued progression of this program towards IND.
Our initial focus is idiopathic small fiber neuralgia, with plans to further expand to other neuropathic pain indications.
Latest preclinical data from Chronic neuropathic pain
Prion disease is a fatal and incurable neurodegenerative disease caused by the misfolding of the prion protein encoded by the PRNP gene. To address prion disease, we are developing zinc finger repressors targeting the PRNP gene.
Our aim is to remove a significant portion of prion protein from neurons to protect them from the toxicity of the misfolded prion protein, potentially preventing the spread and propagation of misfolded prion, and potentially slowing or halting neurodegeneration and disease progression.
Our preclinical data, presented at ASGCT 2023 and the recent Prion 2023 conference, showed that our zinc finger repressors potently and specifically repressed mouse prion in vitro and in vivo, and extended survival in a mouse model of prion disease.
Latest preclinical data from our Prion program
Tauopathies, such as Alzheimer’s disease, are a group of neurodegenerative disorders characterized by the accumulation of abnormal tau protein, which leads to the destabilization of microtubules in neurons and damages neuronal communication.
Our lead product candidate to treat tauopathies, ST-501, utilizes a zinc finger repressor targeting the Tau gene, MAPT. In March 2021, we published preclinical data in Science Advances, showing that tau-targeted ZFRs selectively reduced tau messenger RNA and proteins by 50% to 80% out to 11 months without detectable off-target events.
Latest preclinical data from our Tau program
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder that primarily affects motor neurons responsible for controlling voluntary muscle movement. As the disease progresses, it leads to muscle weakness, atrophy, paralysis, and eventually respiratory failure and death.
ALS has been linked to mutations in the C9ORF72 gene, leading to abnormal protein aggregates and subsequent motor neuron degeneration. To address this disease, in partnership with Alexion (previously partnered with Pfizer), we are developing zinc finger repressors targeting the pathogenic allele of the C9ORF72 gene while preserving expression of the healthy allele.
Latest preclinical data from our ALS program
Synucleinopathies, such as Parkinson’s disease, are a class of neurodegenerative disorders marked by the abnormal aggregation of alpha-synuclein within nerve cells, causing progressive neurological decline. Our lead product candidate for the treatment of synucleinopathies, ST-502, utilizes a zinc finger repressor targeting the alpha-synuclein gene, SNCA.
In 2021, we presented preclinical data at the 15th International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and at the ASGCT Annual Meeting, showing that alpha-synuclein-targeted zinc finger repressors could significantly repress human alpha-synuclein and were well tolerated in vivo.
Latest preclinical data from our alpha-synuclein programOur ZF-activators are able to increase the expression of a gene, which is required to potentially address neurodevelopmental disorders such as autism spectrum disorder and intellectual disability, for which limited therapeutic treatments currently exist. Data presented at ESGCT 2023 showed how ZF-As can be designed to restore normal gene and protein expression of SCN2A in vitro and in vivo. This was accompanied by a poster presentation demonstrating Shank3 gene activation, mediated by ZF-As as a potential therapeutic approach for Phelan-McDermid syndrome.
Latest preclinical data from neurodevelopmental disorder programsIn partnership with Takeda, we are developing potential preclinical genome engineering product candidates to treat Huntington’s Disease. These treatments utilize zinc finger repressors designed to differentially downregulate the mutated disease-causing huntingtin gene (HTT gene) while preserving the expression of the normal version of the gene.
Latest preclinical data from our Huntington’s disease programWe are also investigating cellular therapies using Regulatory T cells for the potential treatment of multiple sclerosis.
Learn more about Multiple Sclerosis