Delving into the Latest Updates on AAV1-FS344 with Synapse

Overview

Basic Info

Drug Type

AAV based gene therapy

Synonyms

AAV1 vectored follistatin gene therapy - Milo Biotechnology, AAV1-Follistatin, rAAV1 CMV huFollistatin 344

+ [2]

Target

FST x MSTN

Mechanism

FST inhibitors(Follistatin inhibitors), MSTN inhibitors(Growth/differentiation factor 8 inhibitors)

Therapeutic Areas

Nervous System DiseasesCongenital DisordersSkin and Musculoskeletal Diseases+ [1]

Active Indication

Muscular Dystrophy, DuchenneMyositis, Inclusion Body

Inactive Indication

Becker Muscular Dystrophy

Originator Organization

Nationwide Children's Hospital

Active Organization

Nationwide Children's Hospital

Milo Biotechnology LLC

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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The proposed clinical trial is an outgrowth of the safety record and functional improvement seen in the BMD follistatin gene therapy trial. In this study the investigators propose to inject AAV1.CMV.huFS344 at a total dose of 2.4E12 vg/kg to six DMD patients. This dose will be divided between gluteal muscles, quadriceps and tibialis anterior. This is a wider distribution of vector than given to BMD patients, who overall improved the distance walked on the 6MWT without adverse events related to viral transduction into a single muscle.

Start Date01 Jan 2015

Sponsor / Collaborator

Nationwide Children's Hospital

[+1]

NCT01519349 / CompletedPhase 1IIT

Phase I Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis.

The investigators are performing a gene therapy clinical trial in Becker muscular dystrophy (BMD) and sporadic inclusion body myositis (sIBM) patients. Both of these conditions have an important common feature: loss of ability to walk because of weakness of the thigh muscles. The investigators plan to do a gene therapy trial to deliver a gene to muscle called follistatin (FS344) that can build muscle size and strength. If successful, the investigators can increase the size of the thigh muscle and potentially prolong a patient's ability to walk. The gene will be carried into the muscle by a virus called adeno-associated virus (AAV). This virus occurs naturally in muscle and does not cause any human disease, setting the stage for its safe use in a clinical trial.
Presently there is no treatment that can reverse Becker muscular dystrophy or sporadic inclusion body myositis. Only supportive care is currently possible.
In this study, subjects with either of these diseases will have shots of the follistatin gene injected directly into thigh muscle on one (first cohort) or both legs (2nd and 3rd cohort). One hundred and eighty days following the gene delivery, the muscle will undergo biopsy to look closely at the muscle to see if the muscle fibers are bigger. Between the time of the gene transfer and the muscle biopsy, patients will be carefully monitored for any side effects of the treatment. This will include an MRI of the thigh muscle before treatment and at day 180 following treatment. Blood and urine tests, as well as physical examination will be done on the subjects during the screening visit and on days 0, 1, 2, 7, 14, 30, 60, 90, and 180 to make sure that there are no side effects from the gene injections. Sutures will be removed 2 weeks post-biopsy.
Additional blood samples will be collected at 9, 12, 18, and 24 months. Patients will be seen at the end of 1st and 2nd years for a physical exam, assessment of muscle strength and appropriate blood tests.

Start Date01 Jan 2012

Sponsor / Collaborator

Nationwide Children's Hospital

[+1]

100 Clinical Results associated with AAV1-FS344

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100 Translational Medicine associated with AAV1-FS344

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100 Patents (Medical) associated with AAV1-FS344

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48

Literatures (Medical) associated with AAV1-FS344

10 Sep 2024·Genes

Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy.

Article

Author: Gallagher, Thomas ; Flotte, Terence R ; Tang, Qiushi ; Reil, Darcy ; Benson, Janet ; Vyhnal, Kristin K ; Pires-Ferreira, Debora ; Blackwood, Meghan ; Lindborg, Jane A ; Keeler, Allison M ; Fu, Dongtao ; Chichester, Jessica A ; Gruntman, Alisha M

BACKGROUND/OBJECTIVESα-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species.METHODSIn this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 10¹² to 1.3 × 10¹³ vg/kg, bracketing those used in our clinical trials.RESULTSWe found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels.CONCLUSIONSOur results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 10¹³-1 × 10¹⁴ vg/kg, which is within the dose range used for approved rAAV gene therapies. Muscle-targeting strategies could be incorporated when delivering systemic administration of high-dose rAAV gene therapies to increase transduction of muscle tissues and reduce the burden on the liver, especially in diseases that can present with hepatotoxicity such as AAT deficiency.

01 Feb 2022·Human Gene TherapyQ2 · MEDICINE

Short-Term Steroid Treatment of Rhesus Macaque Increases Transduction

Q2 · MEDICINE

Article

Author: Guggino, William B. ; Yanda, Murali K. ; Tomar, Vartika ; Cebotaru, Cristina Valeria ; Cebotaru, Liudmila

Repeat dosing poses a major hurdle for the development of an adeno-associated virus (AAV)-based gene therapy for cystic fibrosis, in part because of the potential for development of an immune reaction to the AAV1 capsid proteins. Here, to dampen the immune response to AAV1, we treated Rhesus monkeys with methylprednisolone before and after the instillation of two doses of AAV1Δ27-264-CFTR into their airways at 0 and 30 days, followed by a single dose of AAV1-GFP on day 60. Animals were euthanized on day 90, except for one monkey that was sacrificed at 1 year. No adverse events occurred, indicating that the two AAV1 vectors are safe. rAAV1-CFTR and AAV1-GFP vector genomes and mRNA transcripts were detectable in all lung sections and in the liver and pancreas at day 90 and after 1 year at levels comparable with animals necropsied at 90 days. The numbers of vector genomes for cystic fibrosis transmembrane regulator (CFTR) and green fluorescent protein (GFP) detected here were higher than those found in the monkeys infected without methylprednisolone treatment that we tested previously.¹ Also, lung surface and keratin 5-positive basal cells showed higher CFTR and GFP staining than did the cells from the uninfected monkey control. Positive immunostaining, also detected in the liver and pancreas, remained stable for at least a year. All animals seroconverted for anticapsid antibodies by 90 days post-treatment. The neutralizing antibody titer declined in the animal necropsied at 1 year. Conclusion: AAV1 safely and effectively transduces monkey airway and basal cells. Both the presence of vector genomes and transduction from AAV1-CFTR and AAV1-GFP virus seen in the monkeys 4 months to 1 year after the first instillation suggest that repeat dosing with AAV1-based vectors is achievable, particularly after methylprednisolone treatment.

01 Dec 2019·Acta Neuropathologica CommunicationsQ2 · MEDICINE

Intrathecal delivery of recombinant AAV1 encoding hepatocyte growth factor improves motor functions and protects neuromuscular system in the nerve crush and SOD1-G93A transgenic mouse models

Q2 · MEDICINE

ArticleOA

Author: Kim, Jin Hong ; Kim, Subin ; Lee, Junghun ; Yu, Seung Shin ; Lee, Nayeon ; Lee, Sang Hwan ; Kim, Sunyoung

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease resulting from motor neuron degeneration that causes muscle weakness, paralysis, and eventually respiratory failure. We investigated whether recombinant adeno-associated virus encoding human hepatocyte growth factor (rAAV-HGF) could generate beneficial effects in two mouse models with neuromuscular problems when intrathecally delivered to the subarachnoid space. We chose AAV serotype 1 (rAAV1) based on the expression levels and distribution of HGF protein in the lumbar spinal cord (LSC). After a single intrathecal (IT) injection of rAAV1-HGF, the protein level of HGF in the LSC peaked on day 14 and thereafter gradually decreased over the next 14 weeks. rAAV1-HGF was initially tested in the mouse nerve crush model. IT injection of rAAV1-HGF improved mouse hindlimb strength and rotarod performance, while histological analyses showed that the length of regenerated axons was increased and the structure of the neuromuscular junction (NMJ) was restored. rAAV1-HGF was also evaluated in the SOD1-G93A transgenic (TG) mouse model. Again, rAAV1-HGF not only improved motor performance but also increased the survival rate. Moreover, the number and diameter of spinal motor neurons (SMNs) were increased, and the shape of the NMJs restored. Data from in vitro motor cortical culture experiments indicated that treatment with recombinant HGF protein (rHGF) increased the axon length of corticospinal motor neurons (CSMNs). When cultures were treated with an ERK inhibitor, the effects of HGF on axon elongation, protein aggregation, and oxidative stress were suppressed, indicating that ERK phosphorylation played an important role(s). Taken together, our results suggested that HGF might play an important role(s) in delaying disease progression in the SOD1-G93A TG mouse model by reducing oxidative stress through the control of ERK phosphorylation.

100 Deals associated with AAV1-FS344

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Becker Muscular Dystrophy	Phase 3	US	Nationwide Children's Hospital	01 Jan 2012
Myositis, Inclusion Body	Phase 3	US	-	-
Muscular Dystrophy, Duchenne	Phase 2	-	Milo Biotechnology LLC	-
Muscular Dystrophy, Duchenne	Phase 2	-	Nationwide Children's Hospital	-
Myositis, Inclusion Body	Phase 2	-	Nationwide Children's Hospital	-
Myositis, Inclusion Body	Phase 2	-	Milo Biotechnology LLC	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02354781 (CTgov)	Phase 1/2	Muscular Dystrophy, Duchenne	3	huFollistatin344 (2.4E12 vg/kg CMV.huFollistatin344)	qbodqitwcc(cbxukuqdpz) = zkwmuigoql jjmpaenbbb (bhvnxdcaii, pevlqhaovz - frhhwfefaz) View more	-	15 Apr 2020
				rAAV1.CMV.huFollistatin344 (2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344)	yzaprviskt(vovwebiycm) = ubyqpoygdp sowwqoixbj (cftjmzmjkd, yebrwyonaz - dknyavdnbs) View more
Pubmed \| Mol Ther Manual	Phase 1	Myositis, Inclusion Body	14	AAV1-FS344	(rplrtapzsd) = rsdymixkem azdlvbfojl (yvyhpoesne )	Positive	05 Apr 2017
				untreated	(rplrtapzsd) = rjqzowhhju azdlvbfojl (yvyhpoesne )