Therapeutic expression of human clotting factors IX and × following adeno‐associated viral vector‐mediated intrauterine gene transfer in early‐gestation fetal macaques

Q2 · BIOLOGY

Article

Author: Johana, Nuryanti ; Ceiler, Jessika ; Tan, Yi Wan ; Mattar, Citra N. Z. ; Schmidt, Manfred ; Biswas, Arijit ; Mcintosh, Jenny ; Waddington, Simon N. ; Ogden, Bryan ; Chan, Jerry K. Y. ; Nathwani, Amit C. ; Choolani, Mahesh ; Gil-Farina, Irene ; Rosales, Cecilia

Adeno-associated viral vectors (AAVs) achieve stable therapeutic expression without long-term toxicity in adults with hemophilia. To avert irreversible complications in congenital disorders producing early pathogenesis, safety and efficacy of AAV-intrauterine gene transfer (IUGT) requires assessment. We therefore performed IUGT of AAV5 or -8 with liver-specific promoter-1 encoding either human coagulation factors IX (hFIX) or X (hFX) into Macaca fascicularis fetuses at ∼0.4 gestation. The initial cohort received 1 × 10¹² vector genomes (vgs) of AAV5-hFIX ( n = 5; 0.45 × 10¹³ vg/kg birth weight), resulting in ∼3.0% hFIX at birth and 0.6-6.8% over 19-51 mo. The next cohort received 0.2-1 × 10¹³ vg boluses. AAV5-hFX animals ( n = 3; 3.57 × 10¹³ vg/kg) expressed <1% at birth and 9.4-27.9% up to 42 mo. AAV8-hFIX recipients ( n = 3; 2.56 × 10¹³ vg/kg) established 4.2-41.3% expression perinatally and 9.8-25.3% over 46 mo. Expression with AAV8-hFX ( n = 6, 3.12 × 10¹³ vg/kg) increased from <1% perinatally to 9.8-13.4% >35 mo. Low expressers (<1%, n = 3) were postnatally challenged with 2 × 10¹¹ vg/kg AAV5 resulting in 2.4-13.2% expression and demonstrating acquired tolerance. Linear amplification-mediated-PCR analysis demonstrated random integration of 57-88% of AAV sequences retrieved from hepatocytes with no events occurring in or near oncogenesis-associated genes. Thus, early-IUGT in macaques produces sustained curative expression related significantly to integrated AAV in the absence of clinical toxicity, supporting its therapeutic potential for early-onset monogenic disorders.-Chan, J. K. Y., Gil-Farina I., Johana, N., Rosales, C., Tan, Y. W., Ceiler, J., Mcintosh, J., Ogden, B., Waddington, S. N., Schmidt, M., Biswas, A., Choolani, M., Nathwani, A. C., Mattar, C. N. Z. Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques.

International Journal of Molecular Sciences

A Novel Murine Model Enabling rAAV8-PC Gene Therapy for Severe Protein C Deficiency

Article

Author: Dardik, Rima ; Livnat, Tami ; Samelson-Jones, Benjamin J. ; Nisgav, Yael ; Kenet, Gili ; Avishai, Einat ; Brutman-Barazani, Tami ; Levy-Mendelovich, Sarina

Severe protein C deficiency (SPCD) is a rare inherited thrombotic disease associated with high morbidity and mortality. In the current study, we established a viable murine model of SPCD, enabling preclinical gene therapy studies. By creating SPCD mice with severe hemophilia A (PROC−/−/F8−), the multi-month survival of SPCD mice enabled the exploration of recombinant adeno-associated viral vector-PC (rAAV8-PC) gene therapy (GT). rAAV8- PC (1012 vg/kg of AAV8-PC) was injected via the tail vein into 6–8-week-old PROC−/−/F8- mice. Their plasma PC antigen levels (median of 714 ng/mL, range 166–2488 ng/mL) and activity (303.5 ± 59%) significantly increased to the normal range after GT compared to untreated control animals. PC’s presence in the liver after GT was also confirmed by immunofluorescence staining. Our translational research results provide the first proof of concept that an infusion of rAAV8-PC increases PC antigen and activity in mice and may contribute to future GT in SPCD. Further basic research of SPCD mice with prolonged survival due to the rebalancing of this disorder using severe hemophilia A may provide essential data regarding PC’s contribution to specific tissues’ development, local PC generation, and its regulation in inflammatory conditions.

News (Medical) associated with AAV8-AIPL1 gene therapy (MeiraGTx)

15 Nov 2023

·www.prnewswire.com

Astellas Announces Data from ASPIRO Study in X-linked Myotubular Myopathy Published in The Lancet Neurology

Preliminary data analysis on ventilator dependence and motor improvement are reported alongside overall safety findings TOKYO, Nov. 15, 2023 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") today announced that The Lancet Neurology published a preliminary data analysis from the ASPIRO trial, evaluating the safety and efficacy of investigational AT132 (resamirigene bilparvovec), an adeno-associated viral vector (AAV) gene replacement therapy designed to deliver a functional human MTM1 gene for the treatment of pediatric patients with X-linked myotubular myopathy (XLMTM). The AT132 IND and ASPIRO trial are currently on clinical hold. The manuscript was first published online on November 15th and will be available in the December 2023 print issue of The Lancet Neurology. Perry B. Shieh, M.D., Ph.D., Professor of Neurology and Pediatrics, University of California Los Angeles, and Principal Investigator for ASPIRO "There is a real need for treatments for these patients. These preliminary data document for the first time that there is potential for gene therapy to provide clinical improvements in patients with XLMTM, including improvement in ventilator dependence and achievement of major motor milestones. Additionally, important issues related to liver health in participants with XLMTM receiving gene therapy have been identified and will continue to require careful evaluation." Richard Wilson, Senior Vice President, Primary Focus Lead, Genetic Regulation, Astellas "We are grateful for the opportunity to share this important analysis. We are focused on patients and the potential impact of gene therapy and are driven to deliver transformational benefits for people living with rare genetic diseases. While we continue our efforts to address the ongoing clinical hold for ASPIRO, this publication serves to provide information that may guide efforts aimed at advancing promising therapies for XLMTM." The manuscript reports data as of February 28, 2022. At the time of this data cut, the study included 24 boys with XLMTM dosed with AT132. An exploratory analysis was conducted of two dosing cohorts (lower-dose at 1.3 x 1014 vg/kg and higher-dose at 3.5 x 1014 vg/kg) who received a single infusion of AT132, compared with a control group comprised of two subjects who were enrolled but not dosed and 12 children from a natural history study. At baseline, all participants were ventilator dependent, three were able to sit independently for 30 seconds, and none had achieved more advanced milestones. By 24 weeks post-dosing, the lower-dose cohort demonstrated an estimated 77.7% (95% CI: 40.22, 115.24) greater reduction in mean hours of ventilator support from baseline compared with controls (p=0.0002). The higher-dose cohort demonstrated an estimated 22.8% (95% CI 6.15, 39.37) greater reduction from baseline compared with controls (p=0.0077). Of the 24 boys dosed in the study, 16 participants, including six at the lower-dose and 10 at the higher-dose, achieved ventilator independence as of the data cut. Five participants at the lower-dose and three participants in the higher-dose cohort were able to walk independently; several other major motor milestones were achieved after gene therapy. There were three deaths in the higher-dose cohort (18%), followed by one death in the lower-dose cohort (14%). All four participants had ongoing hepatic and hepatobiliary serious adverse events (SAEs), which had progressed to cholestatic liver failure at the time of death. Treatment-emergent SAEs were observed in two of the seven participants at the lower-dose, and nine of 17 at the higher-dose. Five of the 20 surviving dosed participants had hepatobiliary SAEs. Of the 14 participants in the non-treated cohort (two in the control group and 12 from a natural history study), none achieved ventilator independence while five were able to sit unassisted for 30 seconds by the end of the 48-week period. No other motor milestones were achieved. These data demonstrate the potential of a therapeutic approach for myotubularin replacement using recombinant AAV gene therapy. About X-linked Myotubular Myopathy XLMTM is a serious, life-threatening, rare neuromuscular disease that is characterized by extreme muscle weakness, respiratory failure and early death. Mortality rates are estimated to be 50 percent in the first 18 months of life. For those patients who survive past infancy, there is an estimated additional 25 percent mortality by the age of 10. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,000 newborn males. XLMTM places a substantial burden of care on patients, families and the healthcare system, including high rates of healthcare utilization, hospitalization and surgical intervention. More than 80 percent of XLMTM patients require ventilator support, and the majority of patients require a gastrostomy tube for nutritional support. In most patients, normal developmental motor milestones are delayed or never achieved. Currently, only supportive treatment options, such as ventilator use or a feeding tube, are available. About AT132 for the treatment of X-linked Myotubular Myopathy Astellas is developing AT132, an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AT132 may provide patients with improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. The preclinical development of AT132 was conducted in collaboration with Genethon (). AT132 has been granted Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the U.S. Food and Drug Administration (FDA), and Priority Medicines (PRIME) and Orphan Drug designations by the European Medicines Agency (EMA). About ASPIRO ASPIRO is a two-part, multinational, randomized, open-label ascending dose trial to evaluate the safety and preliminary efficacy of AT132 in XLMTM patients less than five years of age. Primary endpoints include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function). Secondary endpoints include the burden of disease and health-related quality-of-life, and muscle tissue histology and biomarkers. About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at . About Astellas Gene Therapies Astellas Gene Therapies is an Astellas Center of Excellence developing genetic medicines with the potential to deliver transformative value for patients. Our gene therapy drug discovery engine is built around innovative science, a validated AAV platform, and industry leading internal manufacturing capability with a particular focus on rare diseases of the eye, CNS and neuromuscular system. Astellas Gene Therapies will also be advancing additional Astellas gene therapy programs toward clinical investigation. Astellas Gene Therapies is based in San Francisco, with manufacturing and laboratory facilities in South San Francisco, Calif., Sanford, N.C. and Tsukuba, Japan. Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties. Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice. AT132 is an investigational gene therapy: there is no guarantee that AT132 will receive regulatory approval or become commercially available for XLMTM. SOURCE ASTELLAS PHARMA INC.

Orphan DrugClinical ResultFast TrackClinical Study

22 Nov 2022

·www.businesswire.com

AAV Vectors in Gene Therapy - Pipeline Insight, 2022 - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "AAV vectors in gene therapy - Pipeline Insight, 2022" drug pipelines has been added to ResearchAndMarkets.com's offering. AAV vectors in gene therapy: Overview Out of the several viral vectors that have been used to date for delivering the genes of interest, the Adeno-associated viral (AAV) vector appears to be the safest and effective vehicle and can maintain long-term gene and protein expression following a single injection of the vector. AAV vectors are the leading viral vectors for gene delivery to treat a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs, and harnessing revolutionary biotechnologies have contributed extensively to the growth of the gene therapy field. AAV Vectors in Gene Therapy Emerging Drugs GS010: Gensight Biologics LUMEVOQ (GS010; lenadogene nolparvovec) targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a mitochondrial targeting sequence (MTS) proprietary technology platform, arising from research conducted at the Institut de la Vision in Paris, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV vector (Adeno-Associated Virus). The gene of interest is transferred into the cell to be expressed and produces the functional protein, which will then be shuttled to the mitochondria through specific nucleotidic sequences in order to restore the missing or deficient mitochondrial function. "LUMEVOQ" was accepted as the invented name for GS010 (lenadogene nolparvovec) by the European Medicines Agency (EMA) in October 2018. Valoctocogene roxaparvovec: BioMarin Pharmaceutical Valoctocogene roxaparvovec is an investigational AAV5 gene therapy under regulatory review for the treatment of severe hemophilia A. It is currently in preregistration stage of development. In June 2021, BioMarin resubmitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA). In the United States, BioMarin intends to submit two-year follow-up safety and efficacy data on all study participants from the Phase III GENEr8-1 study to support the benefit/risk assessment of valoctocogene roxaparvovec, as previously requested by the Food and Drug Administration (FDA). BioMarin is targeting a Biologics License Application (BLA) resubmission in the second quarter of 2022, assuming favorable study results, followed by an expected six-month review by the FDA. DTX401: Ultragenyx Pharmaceutical DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-? under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase-? activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. In a Phase I/II clinical study, all nine patients showed a clinical response, with significant reductions in the need for cornstarch and improvements in glucose control and other metabolic parameters compared to baseline. The drug is currently being evaluated in Phase III clinical trial to treat patients with Glycogen storage disease type I. AAV5-RPGR: MeiraGTx AAV-RPGR is an investigational gene therapy for the treatment of patients with X-linked retinitis pigmentosa (XLRP) caused by disease-causing variants in the eye specific form of the RPGR gene (RPGR ORF15). AAV-RPGR is designed to deliver functional copies of the RPGR gene to the subretinal space in order to improve and preserve visual function. MeiraGTx and development partner Janssen are currently conducting a Phase III clinical trial of AAV-RPGR in patients with XLRP with disease-causing variants in RPGR ORF15. Timrepigene emparvovec: Biogen Timrepigene emparvovec is an AAV2 vector administered by subretinal injection, which aims to provide a functioning CHM gene and expression of the REP-1 protein to restore membrane trafficking and thereby slow, stop or potentially reverse decline in vision. Data from the Phase 1/2 studies demonstrated a slower rate of decline in visual acuity in patients treated with timrepigene emparvovec compared to untreated patients in the natural history study. In addition, some patients treated with timrepigene emparvovec showed improvements in visual acuity. The studies also demonstrated that timrepigene emparvovec was generally well tolerated with an acceptable safety profile. The safety and efficacy of a single subretinal injection of timrepigene emparvovec is currently being evaluated in the ongoing Phase III STAR study. AMT 061: UniQure AMT-061 (etranacogene dezaparvovec) is an experimental gene therapy that uniQure is developing to treat hemophilia B. AMT-061 uses a modified and harmless adeno-associated virus 5 (AAV5) to deliver a highly functional copy of the F9 gene, called FIX-Padua, to patients' cells. The FIX-Padua gene version was shown to result in FIX clotting activity eight times greater than that associated with the standard F9 gene. As such, the one-time therapy - administrated directly into the bloodstream - is expected to increase FIX levels, helping to prevent and control bleeds. If approved, the therapy will be marketed globally by CSL Behring, which closed a commercialization and licensing agreement with uniQure in May 2021. UniQure and CSL Behring expect to file a regulatory application to the U.S. Food and Drug Administration (FDA) in early 2022 seeking AMT-061's approval for hemophilia B. Research and Development. RGX-314: REGENXBIO RGX-314 is being investigated as a potential one-time treatment for wet AMD, diabetic retinopathy, and other chronic retinal conditions. RGX-314 consists of the NAV AAV8 vector, which encodes an antibody fragment designed to inhibit vascular endothelial growth factor (VEGF). RGX-314 is believed to inhibit the VEGF pathway by which new, leaky blood vessels grow and contribute to the accumulation of fluid in the retina. REGENXBIO is advancing research in two separate routes of administration of RGX-314 to the eye, through a standardized subretinal delivery procedure as well as delivery to the suprachoroidal space. REGENXBIO has licensed certain exclusive rights to the SCS Microinjector from Clearside Biomedical, Inc. to deliver gene therapy treatments to the suprachoroidal space of the eye. According to the company's pipeline, the drug is currently in the Phase III stage of development. SPK-8011: Spark Therapeutics Investigational SPK-8011, a novel bio-engineered adeno-associated viral (AAV) vector utilizing the AAV-LK03 capsid, also referred to as Spark200, contains a codon-optimized human factor VIII gene under the control of a liver-specific promoter. The Food and Drug Administration (FDA) granted orphan-disease designation and breakthrough therapy designation in the US, while the European Commission has granted orphan designation to SPK-8011. NFS-01: Neurophth Investigational NR082, a novel recombinant adeno-associated viral serotype 2 vector (rAAV2) containing a codon-optimized of NADH-dehydrogenase subunit 4 (ND4) gene under the control of the cytomegalovirus promoter and enhancer, is a novel ophthalmic injection that is being developed for the treatment of Leber hereditary optic neuropathy (LHON) associated with ND4 mutations. It is currently being evaluated in Phase II/III clinical trial. GT 005: Gyroscope Therapeutics GT005 is designed as an AAV2-based one-time investigational gene therapy for GA secondary to AMD that is delivered under the retina. GT005 aims to restore balance to an overactive complement system, a part of the immune system, by increasing production of the CFI protein. Complement overactivation has been strongly correlated with the development and progression of AMD. The CFI protein regulates the activity of the complement system. It is believed that increasing CFI production could dampen the system's overactivity and reduce inflammation, with the goal of preserving a person's eyesight. Gyroscope is also evaluating GT005 in two Phase II clinical trials. Further product details are provided in the report AAV vectors in gene therapy: Therapeutic Assessment This segment of the report provides insights about the different AAV vectors in gene therapy drugs segregated based on following parameters that define the scope of the report, such as: Major Players in AAV vectors in gene therapy There are approx. 70+ key companies which are developing the therapies for AAV vectors in gene therapy. The companies which have their AAV vectors in gene therapy drug candidates in the most advanced stage, i.e. Preregistration include, BioMarin Pharmaceutical. Phases The publisher's report covers around 235+ products under different phases of clinical development like Late stage products (Phase III) Mid-stage products (Phase II) Early-stage product (Phase I) along with the details of Pre-clinical and Discovery stage candidates Discontinued & Inactive candidates Route of Administration Key Players BioMarin Pharmaceutical Gensight Biologics PTC therapeutics Ultragenyx Pharmaceutical MeiraGTx Pfizer Biogen uniQure Pfizer Ultragenyx Pharmaceutical REGENXBIO Biogen Spark therapeuics (Roche) Sarepta therapeutics Neurophth Therapeutics LYSOGENE Gyroscope Therapeutics Nanoscope Therapeutics Homology medicines Ultragenyx Pharmaceutical Passage Bio Freeline therapeutics Astellas Pharma Aspa therapeutics Adrenas Therapeutics ESTEVE Sio Gene Therapies Amicus therapeutics 4D Molecular therapeutics Taysha Gene Therapies Atsena Therapeutics BioMarin Pharmaceutical Abeona Therapeutics REGENXBIO uniQure Taysha Gene Therapies Asklepios BioPharmaceutical Sarepta Therapeutics Abeona Therapeutics Forge Biologics Sangamo therapeuics Bayer LogicBio therapeutics Solid Biosciences Applied Genetic Technologies Spark therapeuics (Roche) Eli lilly and company Lexeo Therapeutics Spark therapeutics Gensight Biologics Alcyone Lifesciences MeiraGTx Audentes therapeutics Vivet Therapeutics Takeda Astellas Gene Therapies Homology Medicines Adverum Biotechnologies Libella Gene Therapeutics Rocket Pharmaceuticals Brain Neurotherapy Bio, Inc. Ocugen Asklepios BioPharmaceutical Neurogene Jaguar Gene Therapy, LLC Axovia Therapeutics Coave therapeutics Novartis/ Arctos medical Novartis/Vedere Bio REGENXBIO Inc. StrideBio Abeona therapeutics Sanofi/ Sirion therapeutics Capsida Biotherapeutics Kriya therapeutics Neurophth Poseida Therapeutics, BridgeBio Pharma DiNAQOR/ Biomarin ViGeneron AskBio/Selecta Biosciences Prevail therapeutics Intas Pharmaceuticals Tenaya Therapeutics Scout Bio therapeutics Ocugen Oyster Point pharmaceuticals Cyprium Therapeutics Solid Biosciences Amicus Therapeutics Coave therapeutics AvantiBio Voyager Therapeutics/ Pfizer Aruvant Sciences Alcyone Lifesciences Gene Therapy Research Institution Co., Ltd. For more information about this drug pipelines report visit https://www.researchandmarkets.com/r/ylu69s .

Phase 3Orphan DrugGene TherapyLicense out/inClinical Result

100 Deals associated with AAV8-AIPL1 gene therapy (MeiraGTx)

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Indication	Highest Phase	Country/Location	Organization	Date
Cone Dystrophy	Phase 3	US	MeiraGTx Ltd.	-
Leber Congenital Amaurosis	Discovery	US	MeiraGTx Ltd.	-
Leber Congenital Amaurosis	Discovery	-	MeiraGTx Ltd.	-
Retinitis Pigmentosa	Discovery	US	MeiraGTx Ltd.	-

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