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 (AD), alpha-synuclein (aSyn) in Parkinson disease (PD) and related disorders, mutated huntingtin in Huntington’s disease (HD), and TAR DNA-binding protein 43 (TDP-43) in Amyotrophic Lateral Sclerosis (ALS), are shown to contribute to neurodegeneration and disease progression.
The presence of TDP-43 proteinopathy, characterized by the accumulation of highly modified and misfolded TDP-43 molecules in the cytoplasm, is a hallmark of various neurodegenerative diseases including ALS. Proposed mechanisms underlying TDP-43 proteinopathies involve disruptions in nuclear-cytoplasmic localization homeostasis, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and increased protein truncation of cytoplasmic TDP-43.
Pathological accumulation of aSyn is the common distinguishing trait amongst the group of brain disorders known as synucleinopathies, which include 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 protein aggregates have been evaluated in preclinical and clinical studies. For example, in ALS, several therapeutic strategies, spanning biologics to small molecules, that directly address TDP-43 pathology are under evaluation. In PD, 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.
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 protein aggregate clearance mechanisms (Figure X).
At Coave, using our ALIGATER™ platform, we have generated a coAAV-based genetic medicine approach to deliver safe, low doses of GBA1 and TFEB precisely targeted to relevant structures (tissues and cells) of the central nervous system (CNS), aiming to activate or restore the autophagy and lysosomal functions to eliminate or prevent the accumulation of toxic protein aggregates associated with neurodegenerative disease.
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 (AD), alpha-synuclein (aSyn) in Parkinson disease (PD) and related disorders, mutated huntingtin in Huntington’s disease (HD), and TAR DNA-binding protein 43 (TDP-43) in Amyotrophic Lateral Sclerosis (ALS), are shown to contribute to neurodegeneration and disease progression.
The presence of TDP-43 proteinopathy, characterized by the accumulation of highly modified and misfolded TDP-43 molecules in the cytoplasm, is a hallmark of various neurodegenerative diseases including ALS. Proposed mechanisms underlying TDP-43 proteinopathies involve disruptions in nuclear-cytoplasmic localization homeostasis, aggregation of ubiquitinated and hyper-phosphorylated TDP-43, and increased protein truncation of cytoplasmic TDP-43.
Pathological accumulation of aSyn is the common distinguishing trait amongst the group of brain disorders known as synucleinopathies, which include 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 protein aggregates have been evaluated in preclinical and clinical studies. For example, in ALS, several therapeutic strategies, spanning biologics to small molecules, that directly address TDP-43 pathology are under evaluation. In PD, 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.
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 protein aggregate clearance mechanisms (Figure X).
At Coave, using our ALIGATER™ platform, we have generated a coAAV-based genetic medicine approach to deliver safe, low doses of GBA1 and TFEB precisely targeted to relevant structures (tissues and cells) of the central nervous system (CNS), aiming to activate or restore the autophagy and lysosomal functions to eliminate or prevent the accumulation of toxic protein aggregates associated with neurodegenerative disease.
ALS is a rare neurodegenerative condition marked by the swift and relentless decline of motor neuron function and survival, resulting in paralysis and ultimately respiratory failure, culminating in death usually within five years after diagnosis. The etiology of ALS remains unknown and non-genetically defined in 90-95% of cases, with no cure .
The incidence of ALS in the US and Europe is approximately 2 in 100,000, equating to approx. 30,000 patients in the US and 50,000 in Europe.
Protein aggregation and dysregulation of the autophagy-lysosome pathway are hallmarks of ALS, with evidence of accumulation of autophagosomes, disrupted lysosomes, and TDP-43 aggregates in patients’ brains (Beckers et al., 2021). Transcription factor EB (TFEB) has emerged as a master regulator of the autophagy lysosomal pathway, and is therefore a promising therapeutic target for clearing toxic aggregates (Napolitano and Ballabio, 2016). Stage-dependent alterations in TFEB expression have been observed in ALS models, with decreased TFEB activity in patient brain samples. TFEB overexpression mediated by gene therapy is anticipated to mitigate toxic protein accumulation thus offering a strategy to halt motor neuron degeneration and impede ALS progression. TFEB represents a crucial avenue for ALS treatment, echoing its significance in other neurodegenerative diseases.
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, MSA, PD and LBD, are characterized by aggregates of a-synuclein, associated with impairment of the autophagy-lysosomal pathway. 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 and transduction of TFEB to deep brain structures to treat various neurodegenerative disorders, starting 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 AAV-based TFEB gene therapy approaches in disease models of MSA and PD.
References
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.
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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.
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We are looking for more talented individuals to join our team.
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INSTITUT DU CERVEAU ET DE LA MOELLE EPINIÈRE – ICM
Hôpital Pitié-Salpêtrière
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75013 Paris