INFIXION’S SCIENTIFIC APPROACH
Neurofibromin is Key
To understand iNFixion Bioscience’s scientific approach to developing a treatment for NF1, it is essential to first understand the critical function of Neurofibromin, the protein produced by the NF1 gene. Research over the past 30 years has led to considerable knowledge regarding Neurofibromin, including its regulatory role in many distinct biological pathways and cell types throughout the body, including neurons, peripheral nerve and immune cells.
For example, Neurofibromin is known to regulate cell/tumor growth and differentiation (via Ras/MEK and mTOR pathways), as well as neuronal functions such as memory formation and pain sensation (via dopamine/cAMP/HCN channels). In addition, it is essential for the proper development of many tissues such as brain, bone, cardiovascular tissue and skin.
Although Neurofibromin’s function is not yet fully understood, its fundamental regulatory role in many different biological processes leads to a wide variety of symptoms when this protein is missing or mutated.
Two Key Principles
Autosomal Dominance & Haploinsufficiency
There are two key genetic principles at the center of understanding how iNFixion Bioscience proposes to treat NF1.
1) Autosomal Dominance: NF1 is classified as an ‘autosomal dominant’ genetic disorder. Autosomal dominance simply means that a mutation (whether inherited from a parent or caused by a spontaneous mutation at conception) exists on just one of the two copies (alleles) of the NF1 gene, but that this ‘single-sided mutation’ is sufficient to cause symptoms to manifest, even though the other copy of the NF1 gene is completely normal. People with an NF1 mutation therefore produce about 50% fully-functional neurofibromin from the normal gene copy, and 50% non-functional (or partially functional) neurofibromin from the mutated copy of the NF1 gene.
2) Haploinsufficiency: Publications have also shown that many (if not all) of the NF1 symptoms are directly the result of Neurofibromin haploinsufficiency. Haploinsufficiency simply means that it is the insufficient quantity of normal Neurofibromin, and not the mutated protein itself, that is the primary mechanism causing NF1 manifestations. The importance of haploinsufficiency in NF1 symptom progression has been demonstrated in a wide range of primary research, a summary of which is now available from Infixion.
Together, autosomal dominance and haploinsufficiency provide the scientific basis for iNFixion Bioscience’s unique approach to treat NF1.
THE INFIXION BIOSCIENCE APPROACH
Increase Functional Neurofibromin in NF1-Critical Cells
Utilizing cutting-edge tools and techniques in gene regulation, gene transcription, protein life-cycle management, pluripotent stem cells, and high-throughput screening, the Infixion Bioscience research focus is to develop a safe and effective drug that enhances the NF1-affected person’s natural ability to generate and/or conserve normal Neurofibromin protein produced by the unmutated, or wild-type, NF1 gene allele. This intra-cellular increase in the amount of fully-functional Neurofibromin has been shown to correct biological pathways regulated by Neurofibromin, and to eliminate or slow NF1 symptoms that result from Neurofibromin haploinsufficiency. Infixion’s research path includes the study of making more of the protein (via transcriptional and translation regulation), as well as slowing down the protein’s normal degradation process.
In summary, all NF1 patients have an insufficient level of normal Neurofibromin in their cells and this contributes to the development of NF1 symptoms. Our mission is to develop a drug that will increase the amount of normal Neurofibromin in NF1 patients, and to validate the impact this has to prevent, reduce or eliminate NF1 symptoms.
NF1 Haploinsufficiency Correction Therapy
For more details on Infixion Bioscience’s rationale for “NF1 Haploinsufficiency Correction Therapy (NF1-HCT)”, please see our 2022 peer-reviewed publication in the Journal of Translational Genetics and Genomics.
iNFixion Bioscience’s Research & Development Pipeline
The goal of iNFixion Bioscience is to develop a safe and effective drug that corrects the underlying driver of NF1 symptoms (protein haploinsufficiency), thereby treating and preventing a wide range of NF1 manifestations, regardless of the specific NF1 mutation. iNFixion is currently working on three distinct programs, each targeting a unique element of the NF1 protein life cycle, from transcriptional regulation to protein degradation.
In order to achieve this objective, iNFixion Bioscience is building a suite of scientific tools to 1) more accurately measure neurofibromin protein levels, 2) screen for compounds that impact the NF1 protein life cycle, and 3) measure the impact of a future iNFixion Bioscience drug in the human body.