Nilotinib in Huntington's Disease

The investigators performed an open label phase I clinical trial using two commercially available doses of Nilotinib (150 and 300mg capsules) in patients with advanced PDD and DLB. These indications have some overlapping pathologies and clinical symptoms and share common plasma and CSF biomarkers, including alpha-Synuclein, Abeta42/40, total Tau and p-Tau. The investigators obtained preliminary data showing that Nilotinib crosses the BBB and is detected in the CSF, suggesting Abl inhibition and downstream target engagement (alpha-Synuclein, Tau and Abeta) in the CNS (pharmacodynamics). Nilotinib increased CSF HVA levels as a downstream biomarker of dopamine metabolism. These data provide feasibility to test Nilotinib in a phase Ib clinical trial to demonstrate safety, tolerability and changes in disease biomarkers in patients with HD. The Huntingtin gene provides the genetic information for a protein that is also called "huntingtin" (Htt). Expansion of CAG (cytosineadenine-guanine) triplet repeats in the gene coding for the Huntingtin protein results in an abnormal protein, mutant Htt (mHTT), which gradually leads to protein accumulation within neurons and neuronal cell damage. Based on preclinical and clinical studies, the investigators hypothesize that Nilotinib will be safe and tolerable in individuals with HD. The level of HVA is significantly reduced in HD patients compared to controls (22), and the investigators expect Nilotinib to increase HVA levels. Nilotinib may also affect CSF level of total Huntingtin proteins and cell death markers, including NSE and S100B. The investigators further hypothesize that the investigators may see evidence of change in cognitive, motor or behavioral outcomes that will help us to build a better clinical development program going forward.

Neurodegenerative diseases, including HD, are a group of genetic and sporadic disorders associated with neuronal death and progressive nervous system dysfunction. Cancer is also a collection of related genetic diseases, in which cells begin to divide without stopping and spread into surrounding tissues. Unlike neurodegeneration, in which no regeneration happens when damaged or aging postmitotic neurons die, damaged cells survive when they should die in cancer, resulting in uncontrolled mitotic cell division to form tumors. Cancerous tumors are malignant as they spread or invade nearby tissues by cellular contiguity or metastasize via blood and/or humoral transport. In neurodegeneration, the spread of disease by contiguity is supported by the hypotheses that toxic or "prion-like" proteins propagate along neuroanatomical pathways leading to progressive spread of disease and cell death. In neurodegeneration, failure of cellular quality control mechanisms leads to inadequate protein degradation via the proteasome or autophagy, resulting in intracellular accumulation of neurotoxic proteins. Consequently, these proteins are secreted from a pre-synaptic neuron and can traverse the synaptic cleft and enter a contiguous post-synaptic neuron. Secreted proteins may not penetrate an adjacent cell via the synapse but they may be re-routed into the cell and recycled via the endosomal system to fuse with autophagic vacuoles like the autophagosome or the lysosome. Microglia, the brain resident immune cells may also phagocytose and destroy toxic proteins. Accumulation of neurotoxic proteins, including alpha-Synuclein (Lewy bodies), beta-amyloid plaques, Tau tangles, Huntingtin, prions and TDP-43 are major culprits in neurodegeneration. These toxic proteins trigger progressive apoptotic cell death leading to loss of many central nervous system (CNS) functions, including mentation, cognition, language, movement, gastrointestinal motility, sleep and many others. The discoveries of toxic protein propagation from cell to cell, leading to progression of neurodegeneration triggered a series of pre-clinical and clinical studies to limit protein propagation via antibodies (active and passive immune therapies) that can capture the protein and destroy it en route to healthy neurons. This approach is fraught with difficulties, including failure to arrest neurocognitive decline and brain edema/inflammation. Manipulation of autophagy is a novel therapeutic approach that focuses on degradation of neurotoxic proteins at the manufacturing site in order to prevent their secretion and propagation. This novel strategy leads to unclogging the cell's disposal machine and degradation of toxic proteins, thus preserving neuronal survival via bulk digestion of abnormal proteins. Preservation of neuronal survival maintains the level of neurotransmitters that are necessary for cognitive, motor and other CNS functions, leading to alleviation of symptoms as well as arrest of neurodegeneration. As neurons are post-mitotic cells, pulsatile autophagy may promote protein degradation and provide an effective disease-modifying therapy for neurodegenerative diseases. Autophagy is a double-edged sword in cancer, either preventing accumulation of damaged proteins and organelles to suppress tumors, or promoting cell survival mechanisms that lead to tumor growth and proliferation. Leukemia and many other cancer treatments have been revolutionized by manipulation of autophagy, which leads to bulk degradation of unwanted or toxic molecules. For example in leukemia, genetic mutations and DNA damage can lead to large numbers of abnormal white blood cells (leukemia cells and leukemic blast cells) to accumulate in the blood and bone marrow, crowding out normal blood cells. Autophagy can lead to the degradation of the products of cancer-causing genes (oncogenes), tumor suppressor genes, damaged DNA and essential components of the cytosol, thereby controlling abnormal mitotic division and limiting tumor growth. Autophagy can also lead to self-cannibalization via promotion of programmed cell death, or apoptosis. Activation of the tumor suppressor p53 in response to DNA damage leads the cell to arrest proliferation, initiate DNA repair, and promote survival. However, if the DNA damage cannot be resolved by p53, it can trigger apoptotic death. Cell division and apoptosis are mediated by signaling mechanisms via the endosomal (early and recycling) system. Tyrosine kinases are activated via auto phosphorylation, triggering various signaling mechanisms that mediate cell division and/or apoptosis. Tyrosine kinase inhibition via de-phosphorylation leads to signaling via the late endosomal-lysosomal pathway, thus increasing autophagic degradation and tumor growth. TKIs have significantly improved the life quality and expectancies in many cancers, including CML. CML is characterized by the translocation of chromosomes 9 and 22 to form the "Philadelphia" chromosome resulting in the expression of a constitutively active Breakpoint Cluster Region-Abelson (BCR-Abl) tyrosine kinase. This oncogenic protein activates intracellular signaling pathways and induces cell proliferation. Our laboratory investigated TKIs that activate autophagy and are FDA-approved for CML, thus significantly reducing research and development efforts and cost by re-purposing for new indications. Abl is activated in neurodegeneration. A fraction of Nilotinib crosses the blood-brain-barrier (BBB), inhibits Abl and facilitates autophagic amyloid clearance, leading to neuroprotection and improved cognition and motor behavior. Mice treated with a much lower dose of these drugs (\<25% of the typical CML dose) show significant motor and cognitive improvement and degradation of alpha-Synuclein, beta-amyloid, Tau and TDP-43 without evidence of increased inflammation. There was also significant reversal of neurotransmitter alterations, including dopamine and glutamate in several models of neurodegeneration. As a modulator of myeloid cells, Nilotinib may also positively regulate neuronal death and produce neuro-restorative effects via increased production of necessary growth factors and proliferation of myeloid-derived glia. Autophagic toxic protein clearance and production of growth factors may restore loss of neurotransmitters, leading to improved motor and cognitive functions. Nilotinib provides a double-edge sword via manipulation of autophagy to inhibit cell division and tumor growth in CML on one hand, and promote toxic protein degradation and neuronal survival in neurodegeneration on the other hand. The investigators propose to perform an open label, Phase Ib, proof of concept study to evaluate the impact of low doses of Nilotinib treatment on safety, tolerability and biomarkers in participants with HD. The investigators propose an adaptive design based on safety and tolerability of 150mg Nilotinib treatment for 3 months. The investigators will first enroll 10 participants who will receive an oral dose of 150mg Nilotinib once daily (group 1) for 3 months. If these participants tolerate 150mg dose of Nilotinib, i.e. with no exacerbation of chorea and behavioral symptoms and no other AEs (i.e. myelosuppression, QTc prolongation, liver/pancreatic toxicity, etc ), an additional 10 new HD participants (group 2) will be enrolled to evaluate the effects of 300 mg dose of Nilotinib for 3 months. The investigators will then compare baseline with the effects of 3-months Nilotinib treatment within each group and between groups (1 and 2). Participants (group 1 and 2) will return for a follow up visit one month after the termination of 3-months treatment with Nilotinib and results will compared to baseline visits and end of study visits. Ten (10) participants will receive an oral dose of 150mg Nilotinib once daily for 3 months (group 1). If this dose is tolerated another 10 participants will receive an oral dose of 300mg Nilotinib once daily (group 2) for 3 months.