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Engineered cell therapy targeting neuroprotective pathways to treat retinal degeneration

Prevailing Challenges

Retinal degeneration, like many other complex diseases, involves progressive failures in multiple systems. Standard approaches targeting one single pathway has historically failed to work. A more sophisticated approach targeting multiple pathways is thus required.

Neuro-glycolysis

Neuroinflammation

Oxidative Stress

Metabolic Stress

The use of stem cells and their secretome for neuroprotection has emerged as novel therapeutic approach over the last decade. However, their success in the clinic has proved limited. In particular, stem cell therapies are confronted with two obstacles

Undetermined cell fate leading to cell differentiation towards a heterogeneous cell population and uncontrolled cell-cell interactions

RESULT

Ganglion cell
Amacrine cell
Bipolar cell
Müller cell

Horizontal cell
Rod photoreceptor
Cone photoreceptor

Unpredictable in-vivo microenviroment leading to unwanted cell-matrix interaction

SIGNAL CUES

MECHANICAL CUES

SPATIAL CUES

CROSS LINKING CHEMISTRIES

Our Science

Cellular Development Platform

At InGel our scientists have discovered a novel cell state, during the cell differentiation process, for the retinal neurons including rods, cones and the ganglion cells. In this state, the cells are fated to only differentiate towards one cell type, therefore achieving high purity, but and the same time are still proliferative and can be expanded to hundred of millions. We named them Precursor Cells.

Unlike multi-potent stem cells that may differentiate towards many cell types, these precursor cells make great therapeutic candidates because they do not encounter the unwanted behaviors from a heterogeneous cell population and messy cell-cell interactions. We can also conduct elegant target engagement studies by isolating the pure cells’ secretome and identify the mechanism of neuroprotection.

Rods

Fetal derived
Confirmed phenotype, morphology
High purity (>95%)
Highly neuroprotective

Cones

Fetal derived
Confirmed phenotype, morphology
High purity (>98%)
High engraftment

RGCs

ESc derived
Confirmed phenotype, morphology
High purity from human, mouse and pig sources

Hydrogel Delivery Platform

The other problem confronting regenerative cell therapy is its delivery in vivo. Many studies have shown that the cellular response varies greatly depending on its microenvironment. Mechanical cues such as the injection shear stress alone will trigger apoptosis. Other factors, such as spatial cues (cell anchorage), chemical cues (healthy vs diseased host tissue environment) also trigger different cell behavior in vivo.

That is why the other key innovation at InGel is the engineering of a biomimetic hydrogel matrix, enabling the in vivo delivery of the retinal neurons. Our material scientists took inspiration from the human eye and engineered a hydrogel that mimics the human vitreous, consisting of only Hyaluronic acid and Gelatin. This elegant and simple design allows for both intravitreal and subretinal injections and can be tuned to exhibit different stiffness and degradation timeline.

STIFFNESS & VISCOSITY

SOFT

STIFF

DEGRADATION TIME

1 DAY

6 MTHS

STIFFNESS & VISCOSITY

SOFT

STIFF

DEGRADATION TIME

1 DAY

6 MTHS

Last, because the matrix is engineered to mimic the human vitreous, the degradation of the hydrogel follows an enzymatic degradation, via collagenase and hyaluronidase already present in the eye. This offers a promising safety profile as the metabolites are constantly being cleared by the human eye.

Disease

We are focused on complex retinal degenerative diseases with high unmet need.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina, the light sensitive membrane that coats the inside of the eyes. Peripheral (and night) vision gradually decreases and eventually is lost; then followed by the loss of central vision, color vision until patients become completely blind.

Dry AMD

A common condition affecting more than ten million patients in the US alone, Dry age-related macular degeneration (AMD) is a slow deterioration of the cells of the macula, often over many years. The macula is the part of the retina that controls sharp, straight-ahead vision. While it doesn’t always cause complete blindness, losing the central vision can make it harder to see faces, read, drive, or do close-up work.

Glaucoma

Glaucoma is a group of diseases that damage the nerve connecting the eye to the brain (the optic nerve). It results in progressive vision loss and eventually blindness. About 3 million Americans have glaucoma but only 50% know they have the condition. This is because glaucoma may not cause any symptoms initially.

Research Platform

Regenesis^TM is a target discovery and validation platform for neuroprotective pathways in the eye. It leverages single cell proteomics profiling for rod photoreceptors and their secretome. By modifying specific gene or gene combo in the pure human rod photoreceptor, InGel is able to isolate protein of neuroprotective significance first in vitro and later in vivo. The in vitro testing stage is high-throughput, as testing can be performed in pure human cone photoreceptor population.

Single Cell Proteomics Profiling