Personalized bio-information leads to personalized interventions
Because every individual is a unique biological organism our research and therapeutic intervention development will vary across patients. A misfolded protein in one person may dictate tests and trials specific to their circumstance, while a second individual with the same disease without this anomaly is approached differently. While the “menu” of interventions for one patient may differ from that of another, Above and Beyond’s approach focuses on hyper-personalized interventions derived from a collection of uniquely innovative methods under development.
Patient “X”: A Case Study
Above and Beyond’s advancement and application of intervention methods is illustrated through a recent engagement with an individual with ALS, Patient “X”. Initially, complete medical data was obtained and evaluated to determine the progression of disease pathology and to determine a procedural plan. Initial steps included:
- Whole genome sequencing to identify potential genetic causes of disease.
- Collection of blood and central spinal fluid to monitor disease course.
- Performing drug screens to identify new treatments specific to Patient “X”.
- Applying innovative cell modeling techniques to detect mutations, describe cell morphology, characterize neurotransmitter function, and advance drug screening.
Based on novel cell-modeling techniques, the following findings and outcomes ensued:
- A novel mutation (M1311V ATP7A) was detected in Patient “X”. This mutation changes how the patient cells process and exchange copper and how they respond to copper levels. Advanced methods led to the development of animal and cellular models of this mutation through the creation of Induced Pluripotent Stem Cell (IPSC) derived motor neurons. These experiments suggested that the M1311V ATP7A mutation might be contributing to the disease.1
- Motor neuron shape and function in Patient “X” differed from those of a control group, in particular they showed reduced branching, a hallmark of many neurodegenerative diseases. Patient “X’s” motor neurons also showed increased sensitivity to glutamate, altering neurotransmitter function.
- These results led to drug-screening efforts to develop drugs that reverse the copper processing defects caused by the M1311V ATP7A mutation and improve neuronal survival. Specifically, Above and Beyond advanced three drug screening programs – virtual, mutation-targeted, and neuron survival-targeted.
Translating path breaking discoveries into leading edge treatments
Above and Beyond utilizes the outcomes of personalized investigation and intervention to drive forward the creation of the next generation of methods and treatment aimed at restoring function in patients with ALS and other neurodegenerative diseases. Advancing drug screening, as illustrated through the engagement with Patient “X,” is one of several path-breaking avenues we are pursuing. Additional experience originating from this application of applied precision medicine include the following:
- Repurposing the drug Riluzole for precise intrathecal (spinal cord) delivery to protect motor neuron health.
- Novel gene therapy for intra-parenchymal (neurons and glial cell tissue). This multi-pronged approach is supported by several distinct efforts to build new techniques and therapies, and includes:
New approach demonstrated in ALS animal models. Safety and toxicity studies are advancing, with an Investigational New Drug (IND) Phase I planned for 2019.
- Repurposing existing drugs for delivery directly into neuro-active tissues.
- Human Stem cell-derived therapies, based on virtual and laboratory-based investigations and trials.
Synopsis of this discovery, “Reduced copper transporter trafficking and synaptic deficits in iPSC-MNs derived from an ALS patient with a novel variant of ATP7A,” can be found here.