SBIR-STTR Award

Development of a Topical Sirna Therapy to Promote Burn Wound Healing Via Depletion of the Novel Microtubule Regulatory, Fidgetin-Like-2
Award last edited on: 3/2/2021

Sponsored Program
SBIR
Awarding Agency
NIH : NIMHD
Total Award Amount
$1,715,927
Award Phase
2
Solicitation Topic Code
NIAMS
Principal Investigator
Abhinav Dey

Company Information

Microcures Inc

105 Sylvar Street
Santa Cruz, CA 95060
   N/A
   info@microcures.com
   www.microcures.com
Location: Multiple
Congr. District: 19
County: Santa Cruz

Phase I

Contract Number: 1R43AR070696-01A1
Start Date: 9/1/2017    Completed: 2/28/2018
Phase I year
2017
Phase I Amount
$224,913
There are ~ 600,000 clinically treated burn wounds in the United States each year. The recovery from these burn wounds involves prolonged healing that can take up to a year or more before there is complete tissue regeneration. In many cases, the burn victim is left with disfiguring scars. Wound healing occurs in three distinct stages: an initial inflammatory phase (Phase 1); a proliferative phase (Phase 2); and a long tissue-remodeling phase (Phase 3) that restores the skin to the pre-wound state. As strategies for wound care have evolved from skin grafts and passive dressings to biopharmaceutical approaches, most innovation has continued to promote only Phase 1, either with new materials that better clean and protect the wounded tissue, or with growth factors and/or other factors that modulate the immune response. These approaches are important for coaxing a wound to enter Phase 2, but do little to for remodeling and repair of the tissue (Phase 3). Additionally, excessive use of growth-factor-containing products has been found to increase lifetime cancer risk in patients1. Thus, to improve patient outcomes there is a need for a safe and effective therapy that expedites both early stages of wound healing (Phases 1 and 2) and results in a more efficiently closed and effectively matured wound (Phase 3). Fidgetin-like 2 (FL2) is a recently discovered regulator of the microtubule cytoskeleton that severs and depolymerizes microtubules. Down-regulation of FL2 expression enhanced microtubule function to promote cell motility in vitro and improved healing both clinically and histologically in murine animal models2. MicroCures aims to develop a topical nanoparticle siRNA treatment to this novel target, FL2 (FL2-NP-si), to directly enhance the wound-closure and dermal maturation function of fibroblasts and keratinocytes thereby addressing, for the first time, the challenge of accelerated healing and tissue repair in acute wounds. Thus, wound healing can occur more rapidly, with high fidelity, resulting in reduction in endured pain, lower risk of infection, shorter hospital stays, and decreased scarring. The goal for this proposed project is to characterize a standard formulation of FL2-NP-si in terms of efficacy and safety in two animal models, Yorkshire pig (Specific Aim 1) and Sprague-Dawley rat (Specific Aim 2), in preparation for IND-enabling studies. Time to wound healing and histopathology at the wound site will be evaluated in both animal models. In addition, whole- animal histopathology and the maximum tolerated dose will be determined in Specific Aim 2. At the end of the project period, we will show that FL2-NP-si is both safe and efficacious for the treatment of burn wounds, and is ready for IND-enabling studies.

Public Health Relevance Statement:
There are approximately 600,000 clinically treated burn wounds in the United States each year, which can take up to a year or more before complete tissue repair. Wound healing occurs in three distinct stages: an initial inflammatory phase (Phase 1); a proliferative phase (Phase 2); and a long tissue remodeling phase (Phase 3) that restores the skin to the pre-wound state; however, most treatments only affect Phase 1 or, more recently, Phase 2. MicroCures, Inc. aims to develop a topical nanoparticle siRNA treatment directed to a novel target, FL2 (FL2-NP-si), to directly enhance the wound-closure (Phase 1 and 2) and dermal maturation (Phase 3) function of fibroblasts and keratinocytes thereby addressing, for the first time, the challenge of accelerated healing and tissue repair in acute wounds.

Project Terms:
Acute; Address; Affect; Animal Model; Animals; Architecture; Biological; Biological Products; Burn injury; cancer risk; Caring; cell motility; Cicatrix; Clinical; Complex; Cytoskeleton; Dermal; Development; Dose; Down-Regulation; effective therapy; Environment; Family suidae; Fibroblasts; Formulation; Goals; Grant; Growth Factor; healing; Histologic; Histopathology; Human; Immune response; improved; In Vitro; in vivo; in vivo Model; Infection; Inflammatory; innovation; Irritants; keratinocyte; Left; Length of Stay; Maximum Tolerated Dose; Medical; Microtubule Depolymerization; Microtubules; Modeling; Mus; nanoparticle; novel; Pain; Patient-Focused Outcomes; Pharmacologic Substance; Phase; pre-clinical; Preparation; Process; Property; Recovery; repaired; Risk; Safety; Site; Skin; Skin graft; Small Interfering RNA; Sprague-Dawley Rats; Sterile coverings; Time; tissue regeneration; tissue repair; Tissues; Toxic effect; Toxicology; United States; wound; wound closure; Wound Healing

Phase II

Contract Number: 2R44AR070696-02A1
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
2019
(last award dollars: 2020)
Phase II Amount
$1,491,014

There are ~ 600,000 clinically treated burn wounds in the United States each year. The recovery from these burn wounds involves prolonged healing that can take up to a year or more before there is complete tissue regeneration. In many cases, the burn victim is left with disfiguring scars. Improving early stages of wound healing has been a major focus for wound healing therapeutics. Wound healing occurs in three distinct stages: an initial inflammatory phase (Phase 1); a proliferative phase (Phase 2); and a long tissue remodeling phase (Phase 3) that restores the skin to the pre-wound state. Most innovation has continued to promote only Phase 1, either with new materials (synthetic and biological) that better clean and protect the wounded tissue, or by modulating the immune response. These approaches are important for coaxing a wound to enter Phase 2, but do little to accelerate the longer proliferative processes of tissue regeneration and remodeling1. Thus, to improve patient outcomes there is a need for a safe and effective therapy that expedites both early stages of wound healing (Phases 1 and 2) and results in a more efficiently closed and effectively matured wound (Phase 3). Fidgetin-like 2 (FL2) is a recently discovered regulator of the microtubule cytoskeleton that severs and depolymerizes microtubules. Down-regulation of FL2 expression enhanced microtubule function to promote cell motility in vitro and improved healing both clinically and histologically in murine animal models2. MicroCures aims to develop a topical nanoparticle siRNA treatment to this novel target (FL2-NP-si; SiFi2) to directly enhance the wound-closure and dermal maturation function of fibroblasts and keratinocytes thereby offering the potential to accelerate wound healing AND improve tissue repair. Thus, wound healing can occur more rapidly, with high fidelity, resulting in reduction in endured pain, lower risk of infection, shorter hospital stays, and decreased scarring. During Phase I, 17% enhancement in burn wound re-epithelialization; 30% wound size reduction; significant improvements in collagen deposition and maturation at the wound site; and increased re-innervation and vascularization were observed in a pig burn model following treatment with SiFi2. This Phase II proposal will initiate steps towards an IND filing, including developing the chemistry, manufacturing, and controls necessary for producing GMP SiFi2. This will be accomplished over three specific aims: (1) initiate a GMP start-up program; (2) evaluate potential toxicity issues in vitro; and (3) directly compare the CMO-produced SiFi2 with material used in Phase I in an in vivo efficacy study.

Public Health Relevance Statement:
There are approximately 600,000 clinically treated burn wounds in the United States each year, which can take up to a year or more before complete tissue repair. Wound healing occurs in three distinct stages: an initial inflammatory phase (Phase 1); a proliferative phase (Phase 2); and a long tissue remodeling phase (Phase 3) that restores the skin to the pre-wound state; however, most treatments only affect Phase 1 or, more recently, Phase 2. MicroCures, Inc. aims to develop a topical nanoparticle siRNA treatment directed to a novel target, FL2 (FL2-NP-si; SiFi2), to directly enhance the wound-closure (Phase 1 and 2) and dermal maturation (Phase 3) function of fibroblasts and keratinocytes thereby offer the potential to accelerate wound healing AND improve tissue repair.

Project Terms:
3-Dimensional; Address; Affect; Animals; Architecture; Bandage; Biological; Biological Assay; Bismuth; Burn injury; cell motility; Chemistry; Cicatrix; Clinical; Clinical assessments; Clinical Pathology; Collagen; comparative efficacy; Contracts; Corrosion; Cytoskeleton; Deposition; Dermal; Development; Down-Regulation; effective therapy; efficacy study; Family suidae; Fibroblasts; Formulation; Goals; Grant; healing; Histologic; Histology; Hydration status; Image; Immune response; improved; In Vitro; in vitro Model; in vivo; in vivo Model; infection risk; Inflammatory; innovation; Investigational New Drug Application; keratinocyte; knock-down; Left; Length of Stay; Medical; Microtubule Depolymerization; Microtubules; Miniature Swine; Modeling; Mus; nanoparticle; nerve supply; novel; Pain; pain reduction; Patient-Focused Outcomes; Pharmaceutical Preparations; Phase; Positioning Attribute; Process; programs; Recovery; repaired; Site; Skin; Small Interfering RNA; standard of care; Therapeutic; therapeutic siRNA; tissue regeneration; tissue repair; Tissues; Toxic effect; United States; Vascularization; wound; wound closure; Wound Healing