ANDREA BALLABIO, MD
Director of Telethon Institute of Genetics and Medicine (TIGEM), Italy
ERWAN BÉZARD, PhD
Research Director, Institute of Neurodegenerative Diseases, University of Bordeaux, France
OLIVIER DANOS, PhD
Chief Scientific Officer, RegenxBio
Head of Neurology, University of Tuebingen, Germany
Head of the Neurosurgery Department at Henri Mondor Medical justify, Paris University (UPEC), France
MARK RICHARDSON, MD PhD
Charles A. Pappas Associate Professor of Neurosciences, Harvard Medical School, US
Head of Department of Clinical Neuroscience at UCL Institute of Neurology (ION)
LAMYA SHIHABUDDIN, PhD
Chief Scientific Officer, 4:59 NewCo, a 5AM Ventures Company
DAVID STANDAERT, MD PhD
John N. Whitaker Professor & Chair of Neurology Clinic, UAB Hospital, Birmingham, Alabama, US
Site-specific conjugation onto capsid proteins enables altering of extracellular capsid sequestration, by blocking the binding of the AAV capsid to extracellular motifs.
Ligands are rationally designed to improve cell and tissue targeting, based on defined ligand-receptor interactions.
Site-specific conjugation of capsid proteins leads to improvement of intracellular AAV capsid trafficking and payload delivery to the nucleus.
Ligand conjugation reduces coAAV exposure to immune reaction and neutralizing antibodies.
The misfolding and accumulation of disease-related proteins are common hallmarks of several neurodegenerative diseases. As examples, beta-amyloid and tau in Alzheimer’s disease, alpha-synuclein (aSyn) in Parkinson disease and related disorders, and mutated huntingtin in Huntington’s disease, are shown to contribute to disease progression and neurodegeneration.
Pathological accumulation of aSyn is the common distinguishing trait amongst the group of brain disorders known as synucleinopathies, which include Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA). These disorders progressively develop neuronal and glial inclusions enriched with misfolded, phosphorylated and insoluble aSyn.
Over the past decade, several treatment strategies directly targeting aSyn have been evaluated in preclinical and clinical studies. These diverse approaches include removal of aggregated aSyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering aSyn gene expression by antisense oligonucleotides or inhibitory RNA.
More recently, several new approaches aiming to harness the natural cellular machinery for degradation of toxic protein aggregates, including aSyn, have been investigated.
The autophagy lysosomal pathway (ALP) is a central cellular pathway enabling the degradation of toxic protein aggregates. Key factors of the ALP, such as Glucocerebrosidase (GBA1) and Transcription Factor EB (TFEB), have been shown to play important roles in aSyn clearance mechanisms (Figure X).
At Coave, using our ALIGATER™ platform, we have generated coAAV based gene therapy delivering a safe, low dose of GBA1 and TFEB precisely in the targeted structures of the central nervous system (CNS), aiming to activate or restore the macro-autophagy and lysosomal functions to eliminate or prevent the accumulation of toxic protein aggregates associated with neurodegenerative disease.
Parkinson’s disease (PD) is a severe and progressive neurodegenerative disorder that affects more than seven million people worldwide.
Population-based genetic studies have recently identified several causative and risk genes for PD. Many of these genes are involved in the normal functioning of lysosomes, a cell organelle containing enzymes responsible for degrading biomolecules.
The GBA1 gene encodes the lysosomal enzyme beta-glucocerebrosidase (GCase), which is needed for the disposal and recycling of glycolipids — a type of cellular lipid component that is known to accumulate with aging. Mutations in the GBA1 gene lead to a deficiency of GCase and are associated with earlier onset of PD, with more severe symptoms, and increased likelihood of progression to dementia. Certain mutations in GBA1 reduces the functionality of GCase, which may favor toxic build-up of alpha-synuclein fibrils resulting from the accumulation of glycolipids.
There are currently no approved therapies that modify the course of PD or the underlying pathological process.
Our gene therapy candidate, CTx-GBA1, utilizes a coAAV vector to deliver a gene sequence encoding functional GCase enzyme. CTx-GBA1 has been optimized for improved transduction and distribution of the GBA1 gene in the key structures (basal ganglia) of the brain involved in Parkinson’s disease and related disorders.
The a-synucleinopathies, Multiple System Atrophy (MSA), Parkinson’s disease (PD) and Lewy Body Dementia (LBD), are characterized by aggregates of a-synuclein, associated with impairment of the autophagy-lysosomal pathway. TFEB is a master regulator of the autophagy lysosomal pathway, a central cellular pathway controlling the degradation of toxic protein aggregates. Overexpression of TFEB via gene therapy demonstrates potential to reduce and prevent the accumulation of toxic protein aggregates1.
Coave, in collaboration with the Institute of Neurodegenerative Diseases (IMN), is using its ALIGATER platform to generate coAAV based gene therapy products to target the delivery of TFEB in deep brain structures to treat various neurodegenerative disorders, starting first with a-synucleinopathies.
A paper2, authored by eminent scientists at IMN, including Erwan Bézard, IMN and INSERM Research Director and world-renowned Dr Andrea Ballabio, Scientific Director, Telethon Institute of Genetics and Medicine (TIGEM), demonstrated effective delivery of TFEB AAV-based gene therapy in disease models of MSA and PD.
Our gene therapy product candidate, CTx-TFEB, utilizes a coAAV vector to deliver a gene sequence encoding functional TFEB transcription factor. CTx-TFEB has been optimized for improved transduction and distribution of the TFEB gene in the key structure of the brain involved in MSA and PD.
Inherited retinal dystrophies are rare ophthalmic pathologies that can be divided into two groups:
Retinitis pigmentosa is the most common form of inherited retinal dystrophy representing 50% of all retinal dystrophies.
While multiple genes are implicated in each of these groups, within each patient or family, only one causative gene is involved.
PDE6b RP is an inherited retinal dystrophy that leads to blindness by midlife and is characterized by the progressive loss of photoreceptors, with or without the loss of retinal pigment epithelium cells.
It is caused by mutation of the PDE6b gene resulting in dysfunctional Rod PDE6, an enzyme found in rod outer segments that plays a key role in the phototransduction cascade in rods (the process by which light is converted into electrical signals). Dysfunction of the PDE6 protein, and in particular its PDE6ß subunit, ultimately leads to death of rod photoreceptor cells, then cone photoreceptor cells, leading to blindness.
Mutation of PDE6b is one of the most prevalent human mutations within autosomal recessive RP and accounts for 2-4% of RP cases.
There are currently no approved treatments for PDE6b RP.
CTx-PDE6b is an AAV5 based gene therapy designed to deliver a full-length non-mutated copy of the functional human PDE6b gene into the subretinal space, where it rapidly induces robust transgene expression and synthesis of functional PDE6b proteins in photoreceptive rods and cones. By effectively providing these cells with a functional protein, CTx-PDE6b may significantly delay or halt retinal degeneration in PDE6ß-deficient patients.
CTx-PDE6b is currently in Phase I/II clinical trials.
A description of the protocol can be found on clinicaltrials.gov
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We are a talented, passionate group of colleagues with a desire to translate innovative science into novel gene therapies for patients with neurodegenerative and ocular diseases and beyond.
We are committed to building a vibrant team combining deep expertise in AAV vector engineering and genetic construct design, innovative and advanced therapeutic product development, and manufacturing.
We are looking for more talented individuals to join our team.
63bis avenue Ledru Rolin
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INSTITUT DU CERVEAU ET DE LA MOELLE EPINIÈRE – ICM
47 bd de l’Hôpital