Smart Nerve Condiuts: A Regulated NGF Delivery System Based on Triple Transfected ADSC's

Funding Type: 
Early Translational II
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Peripheral nerve injury is a disorder that occurs through trauma or surgical resection for cancer, causing significant loss of function and workers lost wages.
The total annual cost for nerve injury treatment is $7 billion in the U.S. alone (American Paralysis Association, 1997). 50,000 peripheral nerve repair procedures/year are performed (National Center for Health Statistics, 1995). If peripheral nerve injury is not treated many patients are left with lifelong disabilities. In the clinical setting these injuries accompany upper and lower extremity trauma and are critical in evaluating for limb preservation. We have become facile at treating these injuries, yet despite some intrinsic capacity for these peripheral nerves to regenerate as well as advances in neurobiology, pathophysiology, and operative management with microsurgery, functional recovery and clinical outcomes after peripheral nerve injuries are still unsatisfactory.
Generally the injury is treated by grafting donor nerve tissue from another part of the body to the damaged area often called an autograft. However, this treatment is not ideal as tissue harvesting create areas that may become numb. Many cases remain untreated.
All neural diseases are complicated and difficult to cure as adult neurons go permanent senescence and do not divide. Therefore, neuron cells that are damaged or die are not replaceable. This is especially true for the central nervous system like in case of spinal cord injury. However, prospect for cure for peripheral nerve injury is not all bleak. There are some discoveries that give new hope for the cure. Stem cells can be used for successful treatment of peripheral nerve injury. Stem cells are pluripotent characterized by their ability for unlimited potential to develop all kinds of tissue types.
Human liposuction is a source of stem cells known as adipose derived stem cells (ADSC). Our lab in the Aesthetic and Plastic Surgery Institute is working to harness the power of stem cells for nerve injury in the rat model but looking forward to translational research. This can be achieved in 2 ways –using this multipotent (they can differentiate into certain lineages but not all kinds of cells) stem cell. These multipotent cells will be converted to pluripotent stem cell (called iPS) by several transcription factors. This iPS will be differentiated into neuron and will be used to compensate the damaged neuron. In other way, we are using ADSC for gene delivery to the injured area. Unlike central nervous system, peripheral nerves have some ability to regenerate in the proper environment. These neuron cells need growth factors which instruct them to grow axons. Among the growth factors, nerve growth factor (NGF) is well characterized. We can deliver growth factor genes using ADSC as a vehicle. In this way, the nerve cells stimulate axon regeneration and bridge the damaged area.

Statement of Benefit to California: 

California is the home of leading research centers and schools including stem cell research funded both by private and public entities. UC, Irvine has a robust stem cell program and recently a new building dedicated to stem cell research bears that testimony.
There are several diseases, where stem cell have the potential for treatment including type1 diabetes, ALS, Spinal cords injury, liver failure and neuronal diseases. Adult neurons generally do not divide. So, once they are lost either by stroke, Parkinson’s (loss of dopaminergic neurons), Alzheimer’s or other kind of brain injury or pathological conditions there is no treatment that can help to regenerate neurons.
Despite central neural system disorders peripheral nerve injury on the other hand is common among workers and injured soldier’s coming back from the war zones. Nerve injury equates to total annual cost of $7 billion in the U.S. alone (American Paralysis Association, 1997), while, there are 50,000 peripheral nerve repair procedures done per year (National Center for Health Statistics, 1995)
Contrary to central nervous systems, peripheral nervous system nerve can regenerate to some extent with appropriate growth factors. We have delivered nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) using HEK-293 cells as a vehicle in a sciatic nerve injury model. Recently, we discovered that fat stem cells can be used as a gene carrier which offers a safe and plentiful domains of cells for translational research. We can isolate adipose derived stem cells (ADSC) from those tissues discarded in surgery or by lipoaspiration. These ADSC adult stem cells will be used as a vehicle for gene delivery to the peripheral nerve injury. Our approach to regenerate peripheral nerves in the sciatic nerve model using rats has been successful. This and other basic or translational work on stem cells will invite various biotech companies to invest more in California. This investment will create jobs (direct and indirect) and keep California’s high ranking in science and technology. It will potentially propel the future of the California economy with more advances in the biomedical field and translatable studies.
Scientists in California have make progress in stem cell research and the California Institute for Regenerative Medicine (CRIM) is indispensible for supporting grants, training etc. Our research has the potential to translate directly to patient care. The spin off for California would be more money and jobs.
Proposition 71 initially provided this investment into this technology, approved by the public and to support this innovative field. The purpose of this proposition was to take this research and promote translational studies. This proposal directly supports this proposition and concept by taking stem cell technology and developing potentially translational studies in peripheral nerve surgery.