SBIR-STTR Award

Organocatalysis for the Treatment of Sickle Cell Disease
Award last edited on: 12/29/14

Sponsored Program
SBIR
Awarding Agency
NIH : NHLBI
Total Award Amount
$2,839,106
Award Phase
2
Solicitation Topic Code
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Principal Investigator
Steven Isaacman

Company Information

Nanometics LLC (AKA: PHD Biosciences)

180 Varick Street Suite 526
New York, NY 10014
Location: Single
Congr. District: 12
County: New York

Phase I

Contract Number: 1R43HL106862-01
Start Date: 6/1/11    Completed: 11/30/11
Phase I year
2011
Phase I Amount
$243,469
One potential therapeutic approach to treat sickle cell disease (SCD) involves the administration of aryl aldehyde-containing small molecules that form Schiff base adducts with hemoglobin (HbS) and prevent sickling. The utility of this approach is inherently limited as the kinetics of Schiff base formation between an aryl aldehyde and 1-amino group of HbS is kinetically slow under physiological conditions. Our approach utilizes benign organic catalysts to create a highly reactive therapeutic (AIC) in situ that reacts with HbS at enhanced rates. In preliminary studies, the addition of just 1 mM catalyst dramatically increased Schiff base adduct formation with Hb, as measured by the changes in oxygen affinity. We hypothesize that this strategy will be clinically useful in reducing the therapeutic doses required for efficacy, thus attenuating the likelihood of adverse effects The two Specific Aims of the proposed project are: (I) determination of the optimum levels of aldehyde and catalyst required to achieve different levels of adduct formation with free Hb in solution and in SS red blood cells, and (II) establish the effect of catalyst on the Ex vivo red blood cell sickling and morphology of SS cells by microscopy, and confirm the influence of catalyst on the degree of Schiff base adduct formation using cation exchange chromatography. Phase II efforts include in vivo evaluations of catalyst influence on efficacy in a murine sickle cell model under hypoxic conditions, pharmokinetic studies including bioavailability, and the study of any adverse effects. We plan to commercialize the AIC, formed by reaction between a benign organic catalyst and aromatic aldehyde, as a novel therapeutic for the treatment of SCD. After completion of Phase II efforts, we will partner with a multinational pharmaceutical company to develop the therapeutics through clinical trials.

Public Health Relevance:
Sickle cell disease (SCD) is a genetic disorder that inflicts over 75,000 Americans and 13 million people worldwide. This project seeks to advance the use of organic catalysts to provide for improved therapeutics that treat sickle cell disease at lower clinical doses.

Thesaurus Terms:
2-Furancarboxaldehyde;4-Aminobenzoic Acid;Adverse Effects;Affect;Affinity;Aldehydes;American;Aminobenzoic Acid;Aminohippuric Acids;Attenuated;Benign;Benzoic Acid, 4-Amino-;Bioavailability;Biologic Availability;Biological Availability;Blood Erythrocyte;Blood Normocyte;Cations;Cell Model;Cells;Cellular Model;Chromatography;Chromatography / Separation Science;Clinical;Clinical Trials;Clinical Trials, Unspecified;Dehydration;Dose;Erythrocytes;Erythrocytic;Evaluation;Exhibits;Fructose;Furaldehyde;Furfural;Genetic Condition;Genetic Diseases;Hb Ss Disease;Hbss Disease;Hemoglobin;Hemoglobin S Disease;Hemoglobin Sickle Cell Disease;Hemoglobin Sickle Cell Disorder;Hereditary Disease;Hypoxia;Hypoxic;In Situ;Kidney;Kinetic;Kinetics;Levulose;Mammals, Mice;Marrow Erythrocyte;Measures;Mice;Microscopy;Molecular Disease;Morphology;Murine;Mus;O Element;O2 Element;Oxygen;Oxygen Deficiency;Paba;Pharmaceutical Agent;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Physiologic;Physiologic Availability;Physiological;Preparation;Reaction;Red Blood Cells;Red Cell;Red Blood Corpuscule;Red Cell Of Marrow;Relative;Relative (Related Person);Research;Reticuloendothelial System, Erythrocytes;Schiff Bases;Sickle Cell;Sickle Cell Anemia;Site;Solutions;Technology;Therapeutic;Toxic Effect;Toxicities;Transgenic Organisms;Treatment Side Effects;Urinary System, Kidney;Adduct;Amino Group;Bioavailability Of Drug;Blood Corpuscles;Body Water Dehydration;Catalyst;Clinical Investigation;Commercialization;Drepanocyte;Genetic Disorder;Hereditary Disorder;Improved;In Vivo;New Therapeutics;Next Generation Therapeutics;Novel Therapeutics;P-Aminobenzoic Acid;Para-Aminobenzoic Acid;Phase 1 Study;Polymerization;Prevent;Preventing;Reaction Rate;Renal;Sickle Rbc;Sickle Cell Disease;Sickle Disease;Sickle Erythrocyte;Sickle Red Blood Cell;Sicklemia;Sickling;Side Effect;Small Molecule;Success;Technological Innovation;Therapy Adverse Effect;Transgenic;Treatment Adverse Effect

Phase II

Contract Number: 2R44HL106862-02A1
Start Date: 6/1/11    Completed: 2/28/15
Phase II year
2013
(last award dollars: 2014)
Phase II Amount
$2,595,637

Sickle cell disease (SCD) is a global health issue that affects ~100,000 Americans and over 13 million people worldwide. The complexity of the disease dictates that a multimodal approach to treatment will likely be needed. SCD is manifested physiologically during acute events of sickle crisis as the distorted red blood cells impede blood flow, causing physiological damage and severe pain. Generally characterized as a molecular disease, SCD exhibits many similarities with the pathophysiology of inflammation and reperfusion injury. As such, various forms of antioxidant therapies are being actively pursued as a new approach to treat SCD. No commercial therapeutic is available to treat or avert acute events of crisis, as the development has been stifled by the high (and toxic) concentration required for efficacy. Acute events are currently only managed with pain medication. Product and Long-Term Goal: Nanometics has developed a new type of multimodal therapeutic, termed AIC- 6020, as a small-molecule medication to be taken by patients at the onset or during sickle crisis. AIC-6020 directly modifies hemoglobin (HbS) to both inhibit sickling and to release a known antioxidant to help attenuate oxidative stress events in the microcirculation by antioxidant/anti-inflammatory mechanisms. AIC-6020 will be the first commercial therapeutic useful to treat acute events and the first multimodal therapeutic for SCD. Technical Innovation: Nanometics has developed a new class of multimodal therapeutics to treat sickle cell disease that incorporates two distinct therapeutic mechanisms into one chemical compound. The lead therapeutic reacts with HbS at stochiometric concentrations by a distinct transaldimination mechanism. Phase I Hypothesis and Specific Aims: The Phase I hypothesis was that AIC-6020 would be more effective and less toxic than 5-hydroxymethyl-2-furfural (5HMF). This hypothesis was successfully validated in vitro, ex vivo and in vivo (mice) where the efficacious concentration of AIC-6020 was >50% lower than that of 5HMF. Phase II Objectives: The Phase II objectives will be to 1) optimize the AIC approach to inhibit sickling at the lowest possible concentrations of AIC-6020, (2) establish the bioavailability of AIC-6020 and determine its toxicological and histopathological profile, and (3) examine the impact of AIC-6020 to attenuate events in the microcirculation that are etiologic to sickle cell disease. Commercial Opportunity: In the US alone, there are ~190,000 emergency room visits annually by patients seeking treatment for acute events of crisis, and ~42% of these visits required hospitalization for an average of 5 days. Additionally, there are ~300,000 babies born each year with sickle cell disease, and as infant death rates in developing countries decrease, the target market of patients is expected to rise dramatically over the next 20 years.

Public Health Relevance:
Sickle cell disease (SCD) is a genetic disorder that affects ~100,000 Americans and 13 million people worldwide. This project seeks to advance the use of a new class of multimodal iminium cation therapeutics for sickle cell disease.

Public Health Relevance Statement:
Sickle cell disease (SCD) is a genetic disorder that affects ~100,000 Americans and 13 million people worldwide. This project seeks to advance the use of a new class of multimodal iminium cation therapeutics for sickle cell disease.

Project Terms:
4-Aminobenzoic Acid; Accident and Emergency department; Acute; Affect; Air; American; Analgesics; Anti-inflammatory; Anti-Inflammatory Agents; Anticoagulants; antioxidant therapy; Antioxidants; Attenuated; Biological Availability; Biotechnology; Blood Circulation; Blood flow; Cations; Chemicals; Chronic; Clinical; Combined Modality Therapy; commercial application; commercialization; Death Rate; deoxyhemoglobin; Developing Countries; Development; Disease; Dose; Erythrocytes; Event; Exhibits; Functional disorder; Furaldehyde; global health; Goals; Hemoglobin; Hemolysis; Hereditary Disease; Hospitalization; In Vitro; in vivo; in vivo Model; infant death; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injection of therapeutic agent; innovation; Lead; Light; Marketing; Microcirculation; Modality; mouse model; Mus; Nitric Oxide; novel strategies; novel therapeutic intervention; Oral; Outcome; Oxidative Stress; Oxides; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 1 study; Physiological; Plasma; polymerization; pre-clinical; Reaction; Reagent; Reperfusion Injury; research study; restoration; Rodent Model; Route; Shapes; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; sickling; Small Business Innovation Research Grant; small molecule; success; Symptoms; synergism; technological innovation; Therapeutic; Time; tissue oxygenation; Transgenic Mice; Transgenic Organisms; Vasodilator Agents; Visit; Work