Evaluating a Novel Enzymatic Modality for the Treatment of Fanconi Anemia

Project Summary 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).