SBIR-STTR Award

Fanconi anemia is an inherited illness caused by faulty Fanconi Pathway genes responsible for repairing DNA damage. It is estimated to afflict 1 in every 100, 000-160, 000 and is characterized by bone marrow failure and malignancies that cause disabling multi-organ disease and drastically diminishes patient life expectancy. Although the molecular mechanisms of Fanconi anemia are complex, recent breakthrough studies indicate that through DNA damage, toxic aldehydes such as formaldehyde and acetaldehyde play a fundamental role in disease pathogenesis. Most importantly, in addition to the Fanconi Pathway, dehydrogenase enzymes have been shown to counteract aldehyde toxicity and protect hematopoietic development and function. At present, no standard therapies are available and treatment is limited to symptomatic management and alleviation of disease burden. These include the use of steroids, hematopoietic growth factors, and recurrent blood transfusions. In more precarious circumstances, hematopoietic stem cell transplant can restore bone marrow function and prolong survival. However, this complex procedure carries intrinsic mortality risk and is limited by donor availability, compatibility, and transplant associated complications. A few emerging strategies such as hematopoietic stimulants and gene therapy are being investigated as potential treatments. While neither strategy addresses underlying sources of genotoxicity, the high number of correctable mutations, graft conditioning requirements, and risk for leukemias present unique feasibility challenges for gene therapy. Given the unclear outlook of emerging treatments and a limited therapeutic pipeline, there is an urgent need to develop novel treatments to improve the well-being of Fanconi patients. To meet this need, Kinetiq Therapeutics, a life science startup based in Texas, is developing an enzyme replacement therapy (ERT) for Fanconi anemia, aimed at mitigating aldehyde toxicity. As part of our early development efforts, our team has developed and characterized an aldehyde dehydrogenase enzyme (designated as KALH21) with high plasma stability and activity against both formaldehyde and acetaldehyde. In this SBIR Phase I proposal, we will conduct proof of concept studies in healthy Sprague Dawley rats to demonstrate the feasibility of KALH21 as an ERT. Following KALH21 intervention, we will quantify the systemic clearance of aldehyde challenges (Aim 1) and establish drug disposition attributes (Aim 2) using mass spectrometry and fluorometry. Once feasibility is established, we plan to conduct additional studies in a future SBIR Phase II to evaluate KALH21 doses/regimens and their corresponding safety, efficacy, and disposition. The successful development of our approach could potentially transform the standard of care for Fanconi anemia and other conditions associated with aldehyde toxicity and metabolism (e.g. aldehyde dehydrogenase deficiency syndrome, ischemic heart disease, and gastro-esophageal cancers).

Public Health Relevance Statement:
Public Health Relevance Fanconi anemia is a rare genetic disorder that primarily affects children and causes congenital deformities, damages the organs, and leads to potentially life-threatening bone marrow failure and cancers. Currently, no standard treatments are available and Fanconi patients rely on symptomatic management, blood transfusions, or bone marrow transplants to alleviate disease burden. To solve these challenges, Kinetiq is developing a novel therapy aimed to degrade the toxic substances linked to disease. Successful development of this treatment will greatly improve patient quality of life and well-being and potentially extend life expectancy. Terms: <0-11 years old; ALDH; Acceleration; Acetaldehyde; Address; Affect; Aldehydes; Animal Model; Animal Models and Related Studies; Biodistribution; Biologic Sciences; Biological Sciences; Bioscience; Birth Defects; Blood; Blood Cell Count; Blood Cell Number; Blood Plasma; Blood Reticuloendothelial System; Blood Sample; Blood Transfusion; Blood specimen; Body Tissues; Bone Marrow; Bone Marrow Grafting; Bone Marrow Reticuloendothelial System; Bone Marrow Transplant; Bone Marrow Transplantation; Bone marrow failure; Cancers; Cardiorenal disease; Cardiorenal dysfunction; Cardiorenal syndrome; Catabolism; Cellular injury; Child; Child Youth; Children (0-21); Clinical; Complex; Congenital Abnormality; Congenital Anatomical Abnormality; Congenital Defects; Congenital Deformity; Congenital Malformation; Congenital Pancytopenia; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; DNA Therapy; Defect; Dehydrogenases; Development; Disabling; Disease; Disorder; Dose; Drug Kinetics; Drug Metabolic Detoxication; Drug Metabolic Detoxification; Drug or chemical Tissue Distribution; Environment; Enzyme Gene; Enzymes; Ethanal; Ethnic Group; Ethnic People; Ethnic Population; Ethnic individual; Ethnicity People; Ethnicity Population; Exhibits; Exposure to; Fanconi Anemia; Fanconi Panmyelopathy; Fanconi dysplasia; Fanconi's Anemia; Fluorometry; Food; Formaldehyde; Formic Aldehyde; Future; Gene Transfer Clinical; Genes; Genetic Alteration; Genetic Change; Genetic Intervention; Genetic defect; Genome Stability; Genomic Stability; HSC transplantation; Half-Life; Heart; Hematologic Cancer; Hematologic Malignancies; Hematologic Neoplasms; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoiesis; Hematopoietic; Hematopoietic Cancer; Hematopoietic Cell Growth Factors; Hematopoietic Cellular Control Mechanisms; Hematopoietic Stem Cell Transplant; Hematopoietic Stem Cell Transplantation; Hematopoietic-CGF; Hereditary; Hereditary Disease; Inborn Genetic Diseases; Industrialization; 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Plasma; Plasma Serum; Play; Poison; Predisposition; Prevalence; Primary Erythroid Hypoplasia; Procedures; Property; Protein Replacement Therapy; QOL; Quality of life; Racial Group; Recurrence; Recurrent; Reductases; Regimen; Reticuloendothelial System, Serum, Plasma; Risk; Rodent; Rodentia; Rodents Mammals; Role; SBIR; Safety; Sampling; Skin; Skin Abnormalities; Skin Pigmentation; Small Business Innovation Research; Small Business Innovation Research Grant; Source; Sprague-Dawley Rats; Steroid Compound; Steroids; Stimulant; Susceptibility; Syndrome; Testing; Texas; Therapeutic; Time; Tissue Distribution; Tissues; Toxic Chemical; Toxic Substance; Toxic effect; Toxicities; Transplantation; Unscheduled DNA Synthesis; Weight; Work; aldehyde dehydrogenases; blood cell formation; burden of disease; burden of illness; cardiac ischemia; cell damage; cell injury; cellular damage; commercial application; common symptom; compare intervention; comparison intervention; conditioning; congenital aplastic anemia; 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