▎WuXiEdited by Kant Content Team

Recently, the global cell and gene therapy (CGT) field has seen a series of advancements. Regeneron Pharmaceuticals’ investigational gene therapy DB-OTO, aimed at treating hereditary deafness, restored the hearing of an 11-month-old patient to normal levels within 24 weeks after treatment. AstraZeneca completed its acquisition ofWith many years of deep cultivation in the field of gene editingAn additional equity investment of approximately $140 million by Cellectis. This article will provide a brief introduction to some of the key developments, for readers' reference only.

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———✦R&DProgress✦———

◇ Regeneron announced the Phase 1/2 clinical trial of its investigational gene therapy DB-OTO for the treatment of hereditary deafness.Preliminary Positive Results。One patient received DB-OTO treatment at 11 months old and their hearing recovered to normal levels within 24 weeks, while another patient who received the therapy at age 4 also showed initial improvement in hearing 6 weeks after treatment.Both children were hospitalized due toOTOFChildren with severe hereditary deafness caused by genetic mutations, among whom an 11-month-old child receiving treatment is one of the world's earliest patients to receive gene therapy for hereditary deafness.

DB-OTO is an investigational cell-selective adeno-associated virus (AAV) gene therapy designed to deliver via AAV vectorOTOFA healthy copy of the gene is delivered to the cochlear hair cells, forOTOFPatients with congenital profound hearing loss caused by genetic mutations are provided with lasting physiological hearing.Previously, DB-OTO has received the FDA's Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation.

◇ Freeline Therapeutics announced the ongoing Phase 1/2 GALILEO-1 trial of its investigational gene therapy FLT201.Latest Clinical Data. The results announced this time show,FLT201 significantly reduced lyso-Gb1 levels in Type 1 Gaucher disease patients who had previously been on long-term approved therapies and had persistently high glucosylsphingosine (lyso-Gb1) levels, which is one of the best predictors of clinical response.In addition, there are initial signs of improvement in patients' bone marrow burden and fatigue. In terms of safety, FLT201 demonstrated a favorable safety and tolerability profile, with no infusion reactions or serious adverse events reported. A slight increase in alanine aminotransferase (ALT) levels was observed in some patients, but this was managed with immunotherapy and did not impact efficacy.

FLT201 is a potential “first-in-class” and “best-in-class” investigational AAV gene therapy for the treatment of adult patients with Type 1 Gaucher disease.This therapy aims to provide a one-time treatment to continuously increase GCase expression and reduce the accumulation of harmful substrates in patients, halting disease progression so that patients do not need lifelong treatment.FLT201 uses Freeline's AAVS3 capsid to introduce a novel gene into hepatocytes, producing a rationally designed GCase variant.In preclinical studies, the half-life of this GCase variant under lysosomal pH conditions was more than 20 times longer than that of wild-type human GCase.In preclinical studies, FLT201 led to high expression of GCase and reduced substrate levels in key tissues.

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◇ Atsena Therapeutics announced new data from the Phase 1/2 clinical trial of its investigational gene therapy ATSN-201 for the treatment of X-linked retinoschisis (XLRS). The data disclosed this time shows,Two of the three patients in the first cohort (low-dose group) began to show extensive improvement in retinoschisis at 8 weeks post-dosing. The schisis continued to improve at week 24 (the latest time point currently available).Improved areas of schisis cavities were observed both inside and outside the subretinal injection site, indicating that AAV.SPR is spreading laterally from the injection site, consistent with the expected characteristics of this novel lateral spreading capsid. Functional improvements were also observed in the same locations where retinal structure improvements occurred. One patient showed vision improvement up to 14 dB, with vision improvement exceeding 7 dB at 38 locations. The U.S. FDA considers an improvement of at least 7 dB at ≥5 pre-specified locations to be clinically significant. All three XLRS patients in this group tolerated ATSN-201 well, with no serious adverse events reported.

The novel diffusive capsid AAV.SPR used in ATSN-201 can spread laterally beyond the subretinal injection site, enabling safe and effective gene delivery to the central retina.(In the retinas of XLRS patients, schisis cavities are primarily concentrated in the central retina). Previous studies have shown that AAV.SPR can effectively deliver payloads to cone cells on the fovea of the retina at clinical doses, without the need for surgical dissection and without causing inflammation.

◇ eyeDNA Therapeutics, a newly established subsidiary of Coave Therapeutics, announced positive 24-month follow-up results from the Phase 1/2 clinical trial evaluating HORA-PDE6b. The results showed favorable efficacy in best-corrected visual acuity (BCVA) and Goldmann visual field (GVF) outcomes at 24 months in the subgroup of patients who received the high dose and had milder symptoms.The BCVA of untreated eyes increased by 0.09 LogMar compared to baseline, while the vision of treated eyes remained stable (+0.02 LogMar).From baseline, the GVF of untreated eyes decreased by more than 300 deg² on average, while treated eyes remained relatively stable. After the 24-month study period, patients tolerated both high and low doses of HORA-PDE6b well.

Long-term data (5 years) from the low-dose group showed that the BCVA of untreated eyes continued to decline, while the BCVA of treated eyes in the same group remained stable compared to baseline.In addition, the blue light full-field stimulus test (FFST) used to evaluate rod cell function continues to show a trend of improvement in light perception thresholds for treated eyes, which is clinically significant.

HORA-PDE6b is an AAV5 vector-based gene therapy for the treatment ofPDE6bRetinitis pigmentosa caused by biallelic mutations in genes.

◇ Neurogene Announces Preliminary Safety and Tolerability Data from the Phase 1/2 Trial of NGN-401, a Gene Therapy for Rett Syndrome. The results show that,At follow-ups of approximately 9 months, 6 months, and 3 months post-treatment, three patients generally tolerated NGN-401 well.Most adverse events are known potential risks of AAV,No signs or symptoms of toxicity related to transgenic overexpression were reported.

NGN-401 is an investigational AAV gene therapy delivering a transgene expressing full-length human methylcytosine-binding protein 2 (MeCP2).NGN-401 Utilizes Neurogene's Proprietary Gene Regulation Technology to Provide Highly Controlled and Consistent MeCP2 Expression, Thereby Avoiding Overexpression-Related Toxicity Associated with Conventional Gene Therapy.

◇ Lineage Cell Therapeutics announced 24-month data from the Phase 1/2a clinical trial of its allogeneic retinal pigment epithelium (RPE) cell therapy RG6501 (OpRegen) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). The results showed,AcceptPatients' retinal outer layer structure and visual function showed sustained improvement for at least two years after OpRegen cell administration. OpRegen cells can support the remaining retinal cells within the GA area by counteracting host RPE cell dysfunction and loss.Compared with the baseline, the BCVA of 10 patients in cohort 4 increased by an average of 5.5 letters at 24 months after treatment. Among them, five patients with broader OpRegen coverage of GA lesions showed better therapeutic effects, with an average increase of 7.4 letters in BCVA. Optical coherence tomography (OCT) examination revealed that,OpRegen Continues to Show Improvement in Outer Retinal Structure in Patients with Larger GA Lesions.

◇ Acepodia announced preliminary data from the Phase 1 dose-escalation trial of its off-the-shelf CD20-targeted antibody-conjugated allogeneic γδ2 T-cell therapy, ACE1831, for the treatment of non-Hodgkin lymphoma.ACE1831 utilizes NK cell activation receptors highly expressed on γδ T cells to eliminate malignant blood cells, both in vitro and in vivo.The model demonstrated enhanced cytotoxicity against cancer cells.

The results announced this time show,After a single dose (lowest dose) treatment with ACE1831, one out of five patients achieved complete response (CR), and three reached stable disease (SD).Among these patients, 1 CR and 2 SD patients had previously received CD19-targetedChimeric Antigen Receptor (CAR）-T Cell Therapy.Continuous clinical remission was observed within three months after a single dose of ACE1831.The lowest dose of ACE1831 was well tolerated, with no serious adverse events related to ACE1831, including graft-versus-host disease (GVHD), neurotoxicity, high-grade cytokine release syndrome (CRS), or dose-limiting toxicity.

◇ Fate Therapeutics announced that the first patient has been dosed in a Phase 1 clinical trial of its off-the-shelf CD19-targeted CAR-T cell therapy FT819 for the treatment of systemic lupus erythematosus. In addition, the company also released Phase 1 study data of FT819 in treating relapsed/refractory B-cell malignancies (BCM), as well as preliminary clinical observations from a Phase 1 study of its off-the-shelf CD19-targeted CAR natural killer (NK) cell therapy FT522 for treating relapsed/refractory B-cell lymphoma (BCL). The results showed,FT819 and FT522 both induce rapid, deep, and sustained depletion of CD19+ B cells.

◇ Regeneron announces its AAV gene therapy drugRJK002 InjectionReceived clinical trial tacit permission from the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA), with the indication for Amyotrophic Lateral Sclerosis (ALS). According to Regeneron's press release,The RJK series of drugs from the company can "dissolve" aggregated pathogenic proteins, inhibit the further formation of abnormally aggregated proteins, restore the "phase separation" balance of proteins within biological systems, thereby restoring neuronal cell function and achieving treatment for neurodegenerative diseases.

◇ Biotegene Announces First Patient Treated in Phase 1 Clinical Trial of Autologous CAR-T Cell Therapy BG1805 Targeting CLL-1, a Member of the C-Type Lectin Receptor Family, for Relapsed/Refractory Acute Myeloid Leukemia.

———✦Financing, Cooperation, M&A✦———

◇ Cellectis announced that AstraZeneca has completed a $140 million additional investment in Cellectis after receiving approval from the French Ministry of Economy and meeting all other closing conditions.Cellectis Focuses on Developing Candidate Therapies Using Its Gene-Editing Technology TALEN and Its Groundbreaking Electroporation System PulseAgile to Harness the Power of the Immune System to Target and Eliminate Cancer Cells.In November 2023, AstraZeneca and Cellectis announcedReach Strategic Cooperation and Investment Agreement, will jointly collaborate to accelerate the development of up to 10 next-generation cell and gene therapies, primarily focusing on areas with significant unmet medical needs, including oncology, immunology, and rare diseases.

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◇ OverT Bio Announces $16 Million Seed Financing to Expand Discovery Platform Focused on Addressing Key Challenges in Cell Therapy, Enabling Durable Treatments for Advanced Solid Tumors. The company combines cell engineering technologies with big data to address significant unmet medical needs in the solid tumor space. OverT has developed unique massively parallel genetic screening, single-cell multi-omics, and synthetic biology platforms to engineer the next generation of cell therapies.OverT's core platform searches every gene in the genetic information to identify the optimal gene modifications that confer new properties to immune cells. The company has also established similar high-throughput methods to discover new receptors and targets that are both safe and effective.

◇ Nanite announced that it has received $1.8 million in funding from the Bill & Melinda Gates Foundation to design and optimize polymer delivery vehicles for delivering DNA-encoded therapies, enabling long-term production of therapeutic antibodies in vivo.Nanite’s proprietary SAYER platform combines AI-driven polymer design with multi-dimensional in vivo screening, aiming to develop potentially “best-in-class” polymer nanoparticles (PNPs) capable of specific tissue delivery.The SAYER platform has been proven to have high delivery efficiency and tissue specificity, with the potential to overcome the limitations of viral vectors and lipid nanoparticles (LNPs).Nanite's research is of great significance in discovering a safe PNP for the treatment of AIDS, and the company is committed to accelerating the impact of gene therapy on AIDS treatment.

◇ Denovo Biopharma announced that the California Institute for Regenerative Medicine (CIRM)Nearly $12 million in funding, to support the further development of its biomarker-guided brain tumor gene therapy DB107. According to the press release, CIRM awarded a grant to Dr. Noriyuki Kasahara of the University of California, San Francisco School of Medicine (UCSF) and a group of researchers from several universities in California for the clinical phase 1/2 trial of DB107 in treating newly diagnosed high-grade gliomas, including glioblastoma (GBM).

DB107 is a combination therapy consisting of two parts: DB107-RRV (vocimagene amiretrorepvec), a retroviral replicating vector (RRV) for prodrug activator gene therapy, and the oral prodrug DB107-FC (sustained-release 5-fluorocytosine).DB107-RRV is an intratumoral and intravenous RRV that converts orally administered 5FC into the potent chemotherapeutic agent 5-fluorouracil (5-FU) at the tumor site. This therapy can achieve 30 to 50 times the concentration of 5-FU in tumors compared to systemic administration, killing local cells while minimizing systemic exposure and off-target toxicity of 5-FU.

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