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).

Grant Number: 1R43HL176246-01
NIH Institute/Center: NIH
Principal Investigator: Mingju Cao