Tiverton, RI, United States
Tiverton, RI, United States

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Fjord-Larsen L.,Nsgene Inc. | Kusk P.,Nsgene Inc. | Emerich D.F.,Nsgene Inc. | Thanos C.,CytoSolv, Inc. | And 4 more authors.
Gene Therapy | Year: 2012

Nerve growth factor (NGF) is a potential therapeutic agent for Alzheimer's disease (AD) as it has positive effects on the basal forebrain cholinergic neurons whose degeneration correlates with the cognitive decline in AD. We have previously described an encapsulated cell biodelivery device, NsG0202, capable of local delivery of NGF by a genetically modified human cell line, NGC-0295. The NsG0202 devices have shown promising safety and therapeutic results in a small phase 1b clinical study. However, results also show that the NGF dose could advantageously be increased. We have used the sleeping beauty transposon expression technology to establish a new clinical grade cell line, NGC0211, with at least 10 times higher NGF production than that of NGC-0295. To test whether encapsulation of this cell line provides a relevant dose escalation step in delivering NGF for treatment of the cognitive decline in AD patients, we have validated the bioactivity of devices with NGC0211 and NGC-0295 cells in normal rat striatum as well as in the quinolinic acid striatal lesion model. These preclinical animal studies show that implantation of devices with NGC0211 cells lead to significantly higher NGF output, which in both cases correlate with highly improved potency. © 2012 Macmillan Publishers Limited All rights reserved.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I Project continues the development of the choroid plexus (CP) growth factor cocktail for application to biologic hernia meshes to treat the challenging hernia repair market. CP factors represent a broad spectrum of potent biologic molecules that have demonstrated a benefit in the healing of splinted open wounds in diabetic mice, are neuroprotective, and can be harvested from cultured CP epithelium for at least a year. The current project focuses on formulating these factors into coatings that can be applied to porcine derived acellular dermal matrices in an attempt to provide modulation of the inflammatory cascade and subsequent improvement of engraftment. CP factors harvested from culture will be collected, purified, and concentrated into hydrogel coatings. Three markers of potency, VEGF, TIMP-2, and TGF-â, will be assessed by ELISA to characterize the raw materials, as well release profiles of various formulations. Using the rat midline abdominal defect model, coated mesh prototypes will be compared to commercially available products with a focus on histopathological characterization, gene expression within the graft, and mechanical integrity. The experimental design and selected endpoints are expected to provide the foundation for determining potential efficacy and subsequent product development pathways. The broader impact/commercial potential of this project, if successful will address the need of, approximately 200,000-400,000 patients annually who are associated with impaired healing, poor engraftment of traditional hernia meshes, and recurrence rates as high as 65%. With very high rates of primary repair failure, as well as hernia developing from simple laparotomy, there is a significantly large unmet clinical need resulting in a market size of approximately $1.7B. A successful translation into the clinic will result in a product that improves hernia mesh engraftment by accelerating inflammation and promoting cell migration and extracellular matrix production. Such a product has the potential for an immediate impact in the clinic due to the rise in prevalence of patients with challenging hernia repairs, and lack of available efficacious therapies. The studies proposed here are preliminary steps toward commercialization, with the opportunity to capture a significant portion of the approximately $1.7B market, none of which is currently occupied by growth factor therapies. By demonstrating a therapeutic benefit, this work could be commercialized rapidly through an ongoing partnership to provide near-term benefit to patients with impaired healing.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 150.00K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I Project continues the development of the choroid plexus (CP) growth factor cocktail for application to biologic hernia meshes to treat the challenging hernia repair market. CP factors represent a broad spectrum of potent biologic molecules that have demonstrated a benefit in the healing of splinted open wounds in diabetic mice, are neuroprotective, and can be harvested from cultured CP epithelium for at least a year. The current project focuses on formulating these factors into coatings that can be applied to porcine derived acellular dermal matrices in an attempt to provide modulation of the inflammatory cascade and subsequent improvement of engraftment. CP factors harvested from culture will be collected, purified, and concentrated into hydrogel coatings. Three markers of potency, VEGF, TIMP-2, and TGF-â, will be assessed by ELISA to characterize the raw materials, as well release profiles of various formulations. Using the rat midline abdominal defect model, coated mesh prototypes will be compared to commercially available products with a focus on histopathological characterization, gene expression within the graft, and mechanical integrity. The experimental design and selected endpoints are expected to provide the foundation for determining potential efficacy and subsequent product development pathways.

The broader impact/commercial potential of this project, if successful will address the need of, approximately 200,000-400,000 patients annually who are associated with impaired healing, poor engraftment of traditional hernia meshes, and recurrence rates as high as 65%. With very high rates of primary repair failure, as well as hernia developing from simple laparotomy, there is a significantly large unmet clinical need resulting in a market size of approximately $1.7B. A successful translation into the clinic will result in a product that improves hernia mesh engraftment by accelerating inflammation and promoting cell migration and extracellular matrix production. Such a product has the potential for an immediate impact in the clinic due to the rise in prevalence of patients with challenging hernia repairs, and lack of available efficacious therapies. The studies proposed here are preliminary steps toward commercialization, with the opportunity to capture a significant portion of the approximately $1.7B market, none of which is currently occupied by growth factor therapies. By demonstrating a therapeutic benefit, this work could be commercialized rapidly through an ongoing partnership to provide near-term benefit to patients with impaired healing.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 150.00K | Year: 2011

This Small Business Innovation Research (SBIR) Phase I project will focus on the development of a therapeutic gel containing the full complement of naturally occurring growth factors secreted by the choroid plexus (CP) for use in the active wound care market, including problematic superficial skin wounds such as diabetic ulcers. High doses of single recombinant factors have shown limited value in treating these wounds, with long-term side effects manifesting after cumulative exposure to milligram quantities. The unique technology that CytoSolv has developed employs multiple CP proteins to elicit a synergistic ?cocktail? effect that reduces the cumulative exposure to any one protein, while enhancing the pharmacologic impact by involving multiple regenerative pathways. The broader/commercial impacts of this research extend to tissue regeneration, and CytoSolv has initiated preclinical development to treat diabetic ulcers. These wounds are responsible for the majority of lower extremity amputations in the world, and are among the principal reasons for hospitalization of diabetic patients, accounting for 25% of all admissions in the US. Recently developed biologic therapies have not been widely accepted clinically due to inconsistent evidence of useful efficacy. As a result, the problem of managing complications of diabetic ulcers remains a major source of disability and cost to our health care system, with an active wound care market estimated at $20 billion in the US alone, and more than 115 companies delivering products for 5.7M patients. The goal of the current project is to develop an inexpensive, efficacious therapy based on the CP factor technology.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.68K | Year: 2011

DESCRIPTION (provided by applicant): Chronic superficial wounds are difficult to treat and often never completely heal. Diabetic foot complications account for the majority of lower limb amputations in the world, and 25% of all diabetic hospital admissionsin the US. The standard of care for these wounds has been unchanged for decades, and remains reduced weight bearing, debridement, antibiotics, and dressings. Other therapies have been examined, including vacuum-assisted closure devices, biomaterial-baseddressings, and growth factor therapies. Their impact has been marginal, with little clinical improvement over placebo controls, and often with increased risk of complications. Growth factor therapy, while promising, has not translated into dramatic clinical success with high doses of single exogenous factors. For example, Regranex topical gel (high dose recombinant platelet- derived growth factor), improves closure of diabetic ulcers but with an increased retrospective incidence of cancer. CytoSolv, Inc., has developed technology to simultaneously deliver multiple regenerative factors derived from cultured choroid plexus (CP) to accelerate wound healing at low therapeutic doses. These factors are present in the cerebrospinal fluid of normal adults, as the CPforms the blood- cerebrospinal fluid barrier and is involved in growth factor maintenance. Vascular endothelial growth factor, platelet derived growth factor, connective tissue growth factor, and transforming growth factor beta are among hundreds of potentially regenerative factors secreted by the CP. The synergy of the collective activities of CP factors allows CytoSolv's technology to potentially overcome the limitations and side effects of mono-factor therapy by delivering lower doses over reduced treatment duration. Pilot studies using lyophilized CP factors to treat wounds in normal rats revealed faster healing and vastly improved histological quality of healed tissue compared to topical antibiotic controls, including features such as hair follicles and other dermal appendages. These findings, coupled with the impressive portfolio of bioactive agents in the CP secretome, provide support for continued investigation. The potential clinical applications of an acellular CP product are numerous, but diabeticulcers represent the greatest unmet need and our first target. The extent of ischemic disease in these individuals could be well served by the multiple biologic activities contained within the CP transcriptome. The proposal contained within this SBIR application seeks to (i) continue development of a topical product by incorporating factors secreted by the CP in culture supernatant into a non-occlusive dressing that provides at least 24 hours of continuous factor delivery, as determined in vitro; and (ii)assess the formulated product in open wounds created in the splinted db/db mouse model of Type I diabetes. These projects will provide fundamental data within a 6-month time frame that will allow the company to continue its goal developing a topical product to rebuild damage tissue in diabetic ulcers, and may also uncover additional information relevant to the pursuit of alternative disease indications. PUBLIC HEALTH RELEVANCE: The naturally occurring cocktail of bioactive molecules secreted by the choroid plexus is being developed by CytoSolv, Inc., as a topical regenerative product for accelerating superficial wound healing. The factors, which include many that are currently used in high dose mono-therapies to treat various forms of problematic wounds, range in biological activity from inflammation, to angiogenesis, to tissue rebuilding, and have demonstrated the ability to accelerate and improve the quality of wound repair in pilot studies in normal animals. CytoSolv aims to further characterize, formulate, and assess this early stage product in db/db diabetic mice, representing a stringent wound model with inherent healing impairments that mimic the company's target indication, diabetic ulcers.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 180.00K | Year: 2011

This Small Business Innovation Research (SBIR) Phase I project will focus on the development of a therapeutic gel containing the full complement of naturally occurring growth factors secreted by the choroid plexus (CP) for use in the active wound care market, including problematic superficial skin wounds such as diabetic ulcers. High doses of single recombinant factors have shown limited value in treating these wounds, with long-term side effects manifesting after cumulative exposure to milligram quantities. The unique technology that CytoSolv has developed employs multiple CP proteins to elicit a synergistic ?cocktail? effect that reduces the cumulative exposure to any one protein, while enhancing the pharmacologic impact by involving multiple regenerative pathways.

The broader/commercial impacts of this research extend to tissue regeneration, and CytoSolv has initiated preclinical development to treat diabetic ulcers. These wounds are responsible for the majority of lower extremity amputations in the world, and are among the principal reasons for hospitalization of diabetic patients, accounting for 25% of all admissions in the US. Recently developed biologic therapies have not been widely accepted clinically due to inconsistent evidence of useful efficacy. As a result, the problem of managing complications of diabetic ulcers remains a major source of disability and cost to our health care system, with an active wound care market estimated at $20 billion in the US alone, and more than 115 companies delivering products for 5.7M patients. The goal of the current project is to develop an inexpensive, efficacious therapy based on the CP factor technology.


Trademark
CytoSolv, Inc. | Date: 2010-02-09

Pharmaceutical preparations for wounds.


PubMed | CytoSolv, Inc.
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2016

Hydrogel microcapsules have been used for decades to encapsulate cells and treat diseases ranging from neurodegenerative disorders to more systemic applications like Type I Diabetes. This cell encapsulation modality has been developed through more cumulative experiments than perhaps any other, owing to the relative ease of accessing the required materials, the commercial availability of droplet-generating instrumentation, and the mild microenvironment and unique permeability properties of hydrogels that are difficult to attain with alternative encapsulation systems employing thermoplastic materials. Because of their size and shape, microcapsules have an inherent advantage over macroencapsulation devices due to the more favorable surface area to volume ratio, which allows for greater efficiency in the amount of cellular cargo that is entrapped and enhanced nutrient exchange and efflux of secreted products. Unfortunately, with this significant positive benefit comes the caveat of difficult or impractical retrievability, highlighting the paradox that is particularly relevant as differentiated stem cell sources become more readily available. This chapter focuses on several techniques that can be used to evaluate the permeability and pore structure of hydrogel microcapsules, including a simplistic model for describing the diffusive behavior of alginate-polycation-alginate (APA) microcapsules with a liquid core, and an ancillary method to evaluate the ultrastructure of the APA membrane including morphometric analysis.


PubMed | NS Gene and CytoSolv, Inc.
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2016

The choroid plexus (CP) has been explored as a cellular therapeutic due to its broad-ranging secretome and demonstrated longevity in a variety of encapsulation modalities. While the CP organ is normally involved in disease repair processes in the brain, the range of indications that could potentially be ameliorated with exogenous CP therapy is widespread, including diseases of the central nervous system, hearing loss, chronic wounds, and others. The CP can be isolated from animal sources and digested into a highly purified epithelial culture that can withstand encapsulation and transplantation. Its epithelium can adapt to different microenvironments, and depending on culture conditions, can be manipulated into various three-dimensional configurations with distinct gene expression profiles. The cocktail of proteins secreted by the CP can be harvested in culture, and purified forms of these extracts have been evaluated in topical applications to treat poorly healing wounds. When encapsulated, the epithelial clusters can be maintained for extended durations in vitro with minimal impact on potency. A treatment for Parkinsons disease utilizing encapsulated porcine CP has been developed and is currently being evaluated in a Phase I clinical trial. The current chapter serves to summarize recent experience with CP factor delivery, and provides a description of the relevant materials and methods employed in these studies.

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