Tessera Therapeutics Reports Breakthrough Gene Editing Results for Multiple Genetic Diseases
核心洞察
Tessera's RNA Gene Writer (搜索) technology achieved 76% and 70% editing efficiency in hepatocytes for alpha-1 antitrypsin deficiency (搜索) and phenylketonuria (搜索) respectively, with high specificity and durability in non-human primate studies.
Preclinical data for sickle cell disease (搜索) demonstrated greater than 20% editing in long-term hematopoietic stem cells across multiple species, potentially reaching curative thresholds without requiring stem cell transplantation.
The company's proprietary lipid nanoparticle delivery system showed high liver specificity with no off-target activity detected, advancing the potential for in vivo gene editing therapies for multiple genetic disorders.
Tessera Therapeutics (搜索) has unveiled promising new preclinical data demonstrating significant progress across its in vivo Gene Writing programs at the American Society of Gene and Cell Therapy (ASGCT) Annual Meeting in New Orleans. The biotechnology company presented results from multiple genetic disease programs that showcase the potential of its proprietary RNA Gene Writer (搜索) technology to address previously challenging genetic disorders.
Robust Editing Efficiency in Liver Diseases
In studies targeting alpha-1 antitrypsin deficiency (搜索) (AATD), Tessera's RNA Gene Writer (搜索) achieved an estimated 76% editing efficiency in hepatocytes following a single dose of 1.5 mg/kg in non-human primates (NHPs). The technology demonstrated high fidelity with a 195:1 ratio of intended to unintended edits at the SERPINA1 (搜索) locus.
"The ability to achieve durable, highly efficient gene editing in vivo – including in the liver, hematopoietic stem cells, and T cells – positions Tessera to address multiple disease areas," said Michael Severino, M.D., CEO of Tessera Therapeutics (搜索). "As we move closer to the clinic, these results underscore the potential of our Gene Writing and delivery platforms to advance a new class of genetic medicines."
Safety data from the AATD program revealed high specificity of editing to the liver, with minimal activity in other tissues. Among 30 additional tissues tested, only the spleen showed quantifiable levels of editing above background (0.14%). Importantly, no editing was detected in germline tissues, and no off-target activity was observed at other genetic loci.
The durability of the editing was confirmed in a separate NHP study where 80% editing of hepatocytes targeting SERPINA1 (搜索) remained stable for at least six months, supported by genomic DNA analysis and cDNA analysis of edited mRNA transcripts.
In the PiZ mouse model of AATD, the RNA Gene Writer (搜索) achieved 70% genomic correction in hepatocytes at a dose of just 0.05 mg/kg, and 95% correction at 0.5 mg/kg. These corrections corresponded to 92% and 100% correction of serum AAT protein to wild-type, respectively. The treatment resulted in a 75% reduction of AAT aggregates in liver tissue, with less than 5% of liver area occupied by toxic aggregates at 10 weeks post-treatment in the 0.5 mg/kg group.
Phenylketonuria Program Shows Similar Promise
For phenylketonuria (搜索) (PKU), another monogenic liver disease, Tessera's technology achieved an estimated 70% editing of the phenylalanine hydroxylase (搜索) (PAH) locus in NHP hepatocytes at a 2 mg/kg dose. Supporting cDNA analysis confirmed that 67% of PAH mRNA was successfully edited.
In the humanized R408W mouse model of PKU, the RNA Gene Writer (搜索) achieved an estimated 65% correction in hepatocytes at a dose of 0.2 mg/kg, resulting in normalization of plasma phenylalanine levels.
Potential Breakthrough for Sickle Cell Disease
Perhaps most notably, Tessera presented data on its sickle cell disease (搜索) (SCD) program, which could represent a significant advancement in treatment options for this common and severe genetic disorder.
Multiple proof-of-concept studies using Gene Writer formulated in a proprietary lipid nanoparticle (LNP) delivery vehicle demonstrated greater than 20% editing of the hemoglobin beta-globin (搜索) (HBB) gene in long-term hematopoietic stem cells (LT-HSCs) with repeat dosing in two NHP species. Single-cell analysis of hematopoietic stem cells from treated NHPs showed approximately 35-50% of cells had at least one edited HBB gene.
The edited cells maintained durability across multiple loci in NHPs, with beta-2 microglobulin surrogate editing stable for up to 6 months and HBB editing stable for up to 4 months. The edited cells supported long-term self-renewal and multi-lineage development.
In humanized mouse models, the RNA Gene Writer (搜索) achieved approximately 35% in vivo correction of the HBB gene in LT-HSCs from individuals with SCD, and greater than 50% HBB editing in LT-HSCs across multiple donors in a wild-type model.
These results represent a significant step toward a potentially curative, durable, and non-viral approach for treating SCD that would not require stem cell mobilization/transplantation or myeloablative pre-conditioning. Previous human studies have shown that 20% chimerism can reverse the sickle phenotype in patients following allogeneic hematopoietic stem cell transplant.
Advances in In Vivo T-Cell Therapies
Beyond monogenic diseases, Tessera is applying its Gene Writing and LNP delivery platforms to develop in vivo cell therapies for oncology and autoimmune applications.
Proof-of-concept mouse studies demonstrated that a single intravenous infusion of RNA Gene Writer (搜索) delivered in a proprietary LNP successfully generated functional CAR-T cells in vivo targeting CD19 and CD20. In a tumor-bearing xenograft model, this approach led to CD19 CAR-T cell expansion and complete tumor clearance.
In a naïve humanized mouse model, an average of 30% CD20-targeted CAR writing was achieved in resting T cells, resulting in the elimination of circulating human B cells.
Safe and Precise Delivery System
A critical component of Tessera's platform is its proprietary LNP delivery system, which demonstrated excellent tolerability in NHPs with no clinically meaningful elevation in liver enzyme levels and no signs of coagulopathy at doses of 1 and 2 mg/kg.
The company's comprehensive evaluation of its technology's safety profile is a key focus as it moves toward clinical applications. The high specificity and precision of the editing, combined with the favorable safety profile of the delivery system, position Tessera's Gene Writing platform as a potentially transformative approach for genetic medicine.
As Tessera continues to advance its programs toward the clinic, these preclinical results provide strong support for the potential of its Gene Writing platform to address a wide range of genetic disorders with high efficiency, specificity, and durability.