AAV Gene Therapy Publishes Positive Preclinical Data, Direct Intracerebral Injection for Rare Diseases

April 24, 2022 / eMedClub News / -- Lysogene, a clinical-stage gene therapy company, recently announced the publication of a peer-reviewed article in the journal EMBO Molecular Medicine announcing an initial trial of AAV gene therapy for Fragile X syndrome (FXS).
Preclinical results
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Studies have shown that AAV vector delivery of diacylglycerol kinase (DGKk) achieves long-term effects in the treatment of FXS in a mouse disease model
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Fragile X syndrome (FXS) is a rare inherited intellectual disability
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FXS is caused by a lack of the RNA-binding protein FMRP
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This protein plays a key role in the development of synapses, and insufficient or disrupted FMRP production can affect nervous system function, leading to cognitive and behavioral problems in patients
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Diacylglycerol kinase kappa (DGKk) is the major mRNA target of FMRP in cortical neurons and a major regulator of lipid signaling
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Past studies have found that DGKk is downregulated in FMRP-deficient conditions in a mouse model of brain Fmr1-KO, representing a potentially important therapeutic target for FXS
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This published study demonstrates that delivery of a modified, FMRP-independent form of DGKk using an AAV vector corrects diacylglycerol/phosphatidic acid homeostasis and FXS-related behavior in the brain of Fmr1-KO mice by direct intracerebral injection phenotype
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▲ Image source: Lysogene research data revealed that DGKk is an important factor in the pathogenesis of FXS, proving that DGKk gene replacement based on AAV delivery may be a feasible strategy for the treatment of FXS
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Ralph Laufer, CSO at Lysogene, commented: "These preclinical results confirm the efficacy of our innovative approach targeting DGKk for the treatment of FXS, a central nervous system disorder with a high unmet medical need
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We look forward to further preclinical The research provides more support for this strategy
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”▲ Image source: LysogeneLysogene: Focused on CNS AAV gene therapy Lysogene was founded in 2009 and listed on Euronext Paris in 2017
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The company aims to develop a series of AAV gene therapies targeting central nervous system diseases (CNS)
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Company founder Karen Aiach, whose own children have neurodegenerative diseases, is rooted in a deep and compassionate understanding of the impact these diseases have on patients and families
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Lysogene's Direct-to-CNS delivery technology is designed to utilize AAVs specifically targeted to nerve cells and injected directly into the brain or cerebrospinal fluid (CSF)
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The Direct-to-CNS approach has several advantages: The therapy does not need to cross the blood-brain barrier, so more of the drug reaches the intended site of action
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This allows relatively low doses to be used, helping to reduce local and systemic side effects
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Finally, because the therapeutic is delivered directly to the central nervous system, even patients who are immune to the AAV capsid and cannot be administered systemically can benefit from therapy
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▲ Lysogene's technology platform (Image source: Lysogene's official website) The company's pipeline of AAV gene therapy LYS-SAF302 for the treatment of mucopolysaccharidosis type IIIA is undergoing a global multi-center Phase 2/3 clinical trial
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In February 2022, Lysogene reported positive biomarker data and favorable safety data for the therapy in clinical trials at WORLDSymposium™, the annual Lysosomal Disorders Conference
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Recommended reading: Gene therapy overview at the 2022 Lysosomal Disease Annual MeetingYimai Meng broke the news that its AAV therapy LYS-GM101 for GM1 gangliosidosis completed Phase 1/2 in June last year First dose in clinical trial (NCT04273269)
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Recommended reading: Lysogene completes the first patient administration of AAV gene therapy for GM1 gangliosidosisYimai Meng broke the news Advances in technology have enabled AAV to deliver genes broadly in the brain and spinal cord, making AAV particularly suitable for the treatment of neurological disorders
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AAV can achieve a one-time treatment of the disease through various strategies such as gene replacement, gene silencing, gene editing or expressing exogenous antibodies
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Recommended reading: Nature Reviews: Progress and Challenges of AAV Gene Therapy for Nervous System DiseasesYimai New Observation On March 15, gene therapy company SwanBio Therapeutics announced that the U.
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FDA has granted its AAV gene therapy candidate SBT101 orphan drug designation for Treatment of adrenal medullary neuropathy (AMN)
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The IND application for SBT101 has been approved by the FDA, and a randomized, controlled Phase 1/2 clinical trial is expected to be initiated in the second half of this year
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Recommended reading: AAV gene therapy is at the right time: FDA approves two IND applications in one dayYimai Meng broke the news Three novel AAV capsids discovered on the TRACER platform for the development of therapeutics for neurological disorders
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Recommended reading: 1.
7 billion potential agreement with Novartis to unleash the potential of AAV and optimize the next-generation capsidsYimai Meng broke the news Positive data from Phase 1/2 clinical trial in patients with Zheimer's disease
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The therapy is designed to deliver a transgene expressing protective apolipoprotein E2 (APOE2) to the central nervous system of AD patients with two APOE2 alleles to arrest and slow disease progression
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Recommended reading: "Elderly Killer" Strikes, How AAV Gene Therapy Can Fight BackYimai Meng broke the news On February 9th, REGENXBIO demonstrated its AAV gene therapy RGX-111 for the treatment of severe I.
Positive initial data from a phase I/II clinical trial in mucopolysaccharidosis type I (MPS I)
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MPS is a neurodegenerative disease, and RGX-111 is designed to deliver the gene encoding IDUA using an AAV9 vector that has the ability to cross the blood-brain barrier to target the CNS
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Initial data showed that RGX-111 was well tolerated in patients and showed encouraging sustained neurodevelopmental and biomarker activity in the CNS, meeting the trial's primary and secondary endpoints
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Recommended reading: Penetrating the blood-brain barrier! The latest data on the improved version of AAV gene therapy is releasedYimai Meng broke the news On February 7, uniQure announced the expansion of the clinical development of its one-time gene therapy AMT-130 for the treatment of Huntington’s disease, in its European Phase Ib/II clinical trial The first patient was dosed
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AMT-130 is uniQure's first gene therapy focused on the central nervous system, carried by AAV5 vector to specifically silence huntingtin gene microRNA (microRNA), through the company's proprietary miQURE silencing technology, inhibit mutant huntingtin (mHTT) protein production
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Recommended reading: First-class AAV vector delivery, CNS-focused gene therapy completes first patient dosingYimai Meng broke the news Positive early clinical outcomes in deposition disease
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GM2 gangliosidosis is a rare and fatal monogenic neurodegenerative genetic disorder caused by defects in the HEXA or HEXB genes encoding two subunits of β-hexosaminidase A (Hex A)
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TSHA-101 is the first AAV gene therapy that supports the use of bicistronic vectors to express both HEXA and HEXB genes in natural proportions in humans
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Recommended reading: Treating Rare Diseases! Positive preliminary results of multiple "first" innovative AAV gene therapies -the-treatment-of-fragile-x-syndrome/2.
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