BDNF-expressing bone marrow stem cells promote axonal regeneration in rats with cervical SCI

Wise Young · 02-08-2005, 06:56 AM

The Tuszynski laboratory transplanted bone marrow stem cells into rats with chronic spinal cord injury. The cells supported modest growth of motor and sensory axons. However, when the cells were genetically modified to express brain-derived neurotrophic factor (BDNF), the spinal cords showed significantly greater growth of multiple types of axons. It turns out that the transplanted cells naturally express other neurotrophins (NGF, NT-3). Thus, this suggests that combination neurotrophins improve the ability of bone marrow stem cells to promote regeneration when transplanted into chronically injured spinal cords.

1. Lu, P, Jones, LL and Tuszynski, MH (2005). BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol. 191: 344-60. Department of Neurosciences and Center for Neural Repair, University of California at San Diego, La Jolla, CA 92093-0626, USA. Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery.

Max · 02-10-2005, 10:21 AM

Sigh.....

And its still be years untill it will come to humans

http://stores.ebay.com/MAKSYM-Variety-Store

Wise Young · 02-10-2005, 11:55 AM

Max, this is actually a feasible approach... doing autografts of bone marrow mesenchymal transplants where the cells are transduced to express BDNF. It is something that I hope will be considered for clinical trial soon. Wise.

mk99 · 02-10-2005, 12:12 PM

Dr. Young, in light of the Jessie Gelsinger nightmare, when do you think it would be reasonable and feasible to attempt another gene therapy into human trial? (for any medical condition) Has there been many gene therapy human trials in other countries such as China yet?

Max · 02-10-2005, 01:24 PM

You are uncurable optimist Wise.

Wish God could hear us!

http://stores.ebay.com/MAKSYM-Variety-Store

Wise Young · 02-10-2005, 04:21 PM

Mike, one does not need to use viruses to insert genes into cells. It is worlds different from introducing an adenovirus into the body.

Max, maybe I will get "cured" and become a pessimist.

Wise.

mk99 · 02-10-2005, 05:44 PM

So how difficult would it be to bring into a human trial?

thanks in advance

Schmeky · 02-10-2005, 05:59 PM

Quote:

Max, maybe I will get "cured" and become a pessimist.

Good remark. I could use a big dose of hope about now.

Wise Young · 02-10-2005, 07:58 PM

mike,

We are currently using many non-viral methods to insert genes into cells. If a company were involved, they would simply set aside a couple of million dollars and contract the work out to some group that has expertise in doing this in a FDA compliant way, organize to deliver these cells to the clinical trial centers, and off things will go. Because there are no companies involved, this needs to be done on the cheap and in a laboratory somewhere. Everywhere along the line, you have to convince people to work on the problem and spend time making it rigbht. The difference between a company and a university is that a company pays money while a university has to convince people to do it.

Wise.

02-08-2005, 06:56 AM	#1
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	BDNF-expressing bone marrow stem cells promote axonal regeneration in rats with cervical SCI The Tuszynski laboratory transplanted bone marrow stem cells into rats with chronic spinal cord injury. The cells supported modest growth of motor and sensory axons. However, when the cells were genetically modified to express brain-derived neurotrophic factor (BDNF), the spinal cords showed significantly greater growth of multiple types of axons. It turns out that the transplanted cells naturally express other neurotrophins (NGF, NT-3). Thus, this suggests that combination neurotrophins improve the ability of bone marrow stem cells to promote regeneration when transplanted into chronically injured spinal cords. 1. Lu, P, Jones, LL and Tuszynski, MH (2005). BDNF-expressing marrow stromal cells support extensive axonal growth at sites of spinal cord injury. Exp Neurol. 191: 344-60. Department of Neurosciences and Center for Neural Repair, University of California at San Diego, La Jolla, CA 92093-0626, USA. Bone marrow stromal cells (MSCs) constitute a heterogeneous cell layer in the bone marrow, supporting the growth and differentiation of hematopoietic stem cells. Recently, it has been reported that MSCs harbor pluripotent stem cells capable of neural differentiation and that simple treatment of MSCs with chemical inducing agents leads to their rapid transdifferentiation into neural cells. We examined whether native or neurally induced MSCs would reconstitute an axonal growth-promoting milieu after cervical spinal cord injury (SCI), and whether such cells could act as vehicles of growth factor gene delivery to further augment axonal growth. One month after grafting to cystic sites of SCI, native MSCs supported modest growth of host sensory and motor axons. Cells "neurally" induced in vitro did not sustain a neural phenotype in vivo and supported host axonal growth to a degree equal to native MSCs. Transduction of MSCs to overexpress brain-derived neurotrophic factor (BDNF) resulted in a significant increase in the extent and diversity of host axonal growth, enhancing the growth of host serotonergic, coerulospinal, and dorsal column sensory axons. Measurement of neurotrophin production from implanted cells in the lesion site revealed that the grafts naturally contain nerve growth factor (NGF) and neurotrophin-3 (NT-3), and that transduction with BDNF markedly raises levels of BDNF production. Despite the extensive nature of host axonal penetration into the lesion site, functional recovery was not observed on a tape removal or rope-walking task. Thus, MSCs can support host axonal growth after spinal cord injury and are suitable cell types for ex vivo gene delivery. Combination therapy with other experimental approaches will likely be required to achieve axonal growth beyond the lesion site and functional recovery.

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02-10-2005, 10:21 AM	#2
Max Senior Member Join Date: Jul 2001 Location: Montreal,Province of Quebec, CANADA Posts: 15,036	Sigh..... And its still be years untill it will come to humans http://stores.ebay.com/MAKSYM-Variety-Store

02-10-2005, 11:55 AM	#3
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	Max, this is actually a feasible approach... doing autografts of bone marrow mesenchymal transplants where the cells are transduced to express BDNF. It is something that I hope will be considered for clinical trial soon. Wise.

02-10-2005, 12:12 PM	#4
mk99 Senior Member Join Date: Jul 2001 Location: toronto, canada Posts: 3,494	Dr. Young, in light of the Jessie Gelsinger nightmare, when do you think it would be reasonable and feasible to attempt another gene therapy into human trial? (for any medical condition) Has there been many gene therapy human trials in other countries such as China yet?

02-10-2005, 01:24 PM	#5
Max Senior Member Join Date: Jul 2001 Location: Montreal,Province of Quebec, CANADA Posts: 15,036	You are uncurable optimist Wise. Wish God could hear us! http://stores.ebay.com/MAKSYM-Variety-Store

02-10-2005, 04:21 PM	#6
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	Mike, one does not need to use viruses to insert genes into cells. It is worlds different from introducing an adenovirus into the body. Max, maybe I will get "cured" and become a pessimist. Wise.

02-10-2005, 05:44 PM	#7
mk99 Senior Member Join Date: Jul 2001 Location: toronto, canada Posts: 3,494	So how difficult would it be to bring into a human trial? thanks in advance

02-10-2005, 07:58 PM	#9
Wise Young Administrator Join Date: Jul 2001 Location: New Brunswick, NJ, USA Posts: 37,988	mike, We are currently using many non-viral methods to insert genes into cells. If a company were involved, they would simply set aside a couple of million dollars and contract the work out to some group that has expertise in doing this in a FDA compliant way, organize to deliver these cells to the clinical trial centers, and off things will go. Because there are no companies involved, this needs to be done on the cheap and in a laboratory somewhere. Everywhere along the line, you have to convince people to work on the problem and spend time making it rigbht. The difference between a company and a university is that a company pays money while a university has to convince people to do it. Wise.