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Combining Delivery Routes for a More Effective
Gene Therapy For Infantile NCL
Alejandra	J.	Rozenberg1,	Erik	A.	Lykken2,	Steven	J.	Gray2
1Gene	Therapy,	University	of	North	Carolina	at	Chapel	Hill,	Chapel	Hill,	NC;
2	Pediatrics,	University	of	Texas	Southwestern	Medical	Center,	Dallas,	TX
l
Contact :Steven.Gray@UTSouthwestern.edu
CLN1
BDSRA	2018
III. Intrathecal injection (lumbar
puncture)
Vector will flow through the
cerebrospinal fluid and distribute
throughout the CNS.
Used for the CLN6 and Giant Axonal
Neuropathy (GAN) clinical trials.
I. Direct brain injection
A. The vector is injected into multiple areas of the
brain. Approach of the CLN2 clinical trial with AAV.
B. Vector can be injected into the cerebrospinal fluid
(CSF) that surrounds and runs through the brain and
spinal cord (into ventricles or into the cisterna magna).
II. Intravenous injection
Uses a vector that can reach the brain by
crossing the Blood-Brain barrier.
Utilized in Spinal Muscular Atrophy (SMA)
and MPS IIIA clinical trials.
Getting the vector to the brain
There are three main delivery routes:
Cerebrospinal
fluid
Brain
Spinal	
Cord
— Each form of Batten (Neuronal Ceroid Lipofuscinoses -
NCL-) is caused by a mutation in the patient’s DNA that
renders a gene defective.
— Gene transfer is the idea of replacing the defective
gene with a working copy of the gene.
What is gene therapy?
— Gene transfer should correct the disease at the source
of the problem, rather than just treating symptoms.
— “Gene transfer” becomes gene therapy when the new
gene fixes some aspect of the disease and it helps the
patient.
— Since the gene is corrected, one treatment can be a
permanent fix.
— The new healthy copy of the
gene has to be delivered to
the cells. Anything that is used
to move the DNA into the cells
is called a vector.
— The	most	prominent	and	
widely	used	vector	for	
Batten	Disease	and	other		
brain	disorders	is	the	
Adeno-Associated	Virus	
(AAV).
Used	in	over	75	human	
clinical	trials,	including	
Parkinson’s,	Batten	and		
Canavan Disease.
How does gene transfer work?
cell	makes	protein	
using	new	gene
— Our results support a rationale for dosing patients by both routes
simultaneously.
— Our preliminary results in mice also suggest the possibility of treating
moderately affected patients.
Gene Therapy in INCL mice
Conclusions
Other NCL efforts in the Gray Lab
— CLN2:	testing	gene	therapy	in	a	mouse	model.
— CLN7:	testing	gene	therapy	in	a	mouse	model.
— CLN5	and	CLN6:	collaboration	with	David	Palmer	in	New	Zealand,	in	sheep	
models.
Cell	with	
defective	gene
Introduction	of	
healthy	gene
Cell	function	
restored
Contributors at UNC
Courtney Santos
Khushnood Faraz
UNC Vector Core
UNC Mouse Behavioral
Phenotyping Core
Collaborators
Mark Sands (WashU)
Jonathan Cooper (UCLA)
Sandra Hofmann (UTSW)
Symptoms
Low	Dose
High	Dose
Untreated	
INCL	mice	
1	week-IT	
4	week-IT
12	week-IT
20	week-IT	
26	week-IT
Untreated	
normal	mice	
lifespan
20	week	
Dual-route	
treatment	
In	progress
Age	at	time	of	
intervention-route	
Treatment comparison in mice
LD (Low Dose)
HD (High Dose)
Experimental design:
single time point treatment
IT: Intrathecal (lumbar puncture)
IV: Intravenous (tail vein)
IT HD
6 months 8 months3 months
IT HD
1 month1 weekBirth
4.5 months
IT LD
pre-symptomatic early-symptomatic symptomatic premature death
✾IT HD + IV HD
Combination	
therapy:
Results with intrathecal route
— While mice treated at a later stage in the disease with
the lower dose did not show any significant benefits,
treatment with this same dose extended lifespan and
improved behavior for mice at earlier stages.
— Treatment with a higher dose provided significant
benefits in the early-symptomatic mice and greatly
improved outcomes for younger mice.
— We established that 1) early treatment is better; and
2) higher dose is better.
— Although treating earlier is better, without newborn screening, the
majority of INCL patients in the near future will be treated at the
early-symptomatic or symptomatic stages.
Intrathecal and intravenous dual
treatment: Why combine both?
— The IT dose is limited by the volume that can be safely
injected into the intrathecal space. By combining it with an
intravenous (IV) dose, we hypothesized that it could further
improve survival and behavior in early-symptomatic mice.
Results with combination therapy
— The dual treatment provided significant benefits in behavior
and survival over the intrathecal route alone in early-
symptomatic mice.
— We continue evaluating this cohort (with some of them
currently reaching 16.3 months of age).
— We	are	further	exploring	combination	treatment	in	younger	mice.
IT HD
IT LD
IT HD
IT LDIT HD
IT LD

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2018 BDSRA Gray CLN1

  • 1. Combining Delivery Routes for a More Effective Gene Therapy For Infantile NCL Alejandra J. Rozenberg1, Erik A. Lykken2, Steven J. Gray2 1Gene Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC; 2 Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX l Contact :Steven.Gray@UTSouthwestern.edu CLN1 BDSRA 2018 III. Intrathecal injection (lumbar puncture) Vector will flow through the cerebrospinal fluid and distribute throughout the CNS. Used for the CLN6 and Giant Axonal Neuropathy (GAN) clinical trials. I. Direct brain injection A. The vector is injected into multiple areas of the brain. Approach of the CLN2 clinical trial with AAV. B. Vector can be injected into the cerebrospinal fluid (CSF) that surrounds and runs through the brain and spinal cord (into ventricles or into the cisterna magna). II. Intravenous injection Uses a vector that can reach the brain by crossing the Blood-Brain barrier. Utilized in Spinal Muscular Atrophy (SMA) and MPS IIIA clinical trials. Getting the vector to the brain There are three main delivery routes: Cerebrospinal fluid Brain Spinal Cord — Each form of Batten (Neuronal Ceroid Lipofuscinoses - NCL-) is caused by a mutation in the patient’s DNA that renders a gene defective. — Gene transfer is the idea of replacing the defective gene with a working copy of the gene. What is gene therapy? — Gene transfer should correct the disease at the source of the problem, rather than just treating symptoms. — “Gene transfer” becomes gene therapy when the new gene fixes some aspect of the disease and it helps the patient. — Since the gene is corrected, one treatment can be a permanent fix. — The new healthy copy of the gene has to be delivered to the cells. Anything that is used to move the DNA into the cells is called a vector. — The most prominent and widely used vector for Batten Disease and other brain disorders is the Adeno-Associated Virus (AAV). Used in over 75 human clinical trials, including Parkinson’s, Batten and Canavan Disease. How does gene transfer work? cell makes protein using new gene — Our results support a rationale for dosing patients by both routes simultaneously. — Our preliminary results in mice also suggest the possibility of treating moderately affected patients. Gene Therapy in INCL mice Conclusions Other NCL efforts in the Gray Lab — CLN2: testing gene therapy in a mouse model. — CLN7: testing gene therapy in a mouse model. — CLN5 and CLN6: collaboration with David Palmer in New Zealand, in sheep models. Cell with defective gene Introduction of healthy gene Cell function restored Contributors at UNC Courtney Santos Khushnood Faraz UNC Vector Core UNC Mouse Behavioral Phenotyping Core Collaborators Mark Sands (WashU) Jonathan Cooper (UCLA) Sandra Hofmann (UTSW) Symptoms Low Dose High Dose Untreated INCL mice 1 week-IT 4 week-IT 12 week-IT 20 week-IT 26 week-IT Untreated normal mice lifespan 20 week Dual-route treatment In progress Age at time of intervention-route Treatment comparison in mice LD (Low Dose) HD (High Dose) Experimental design: single time point treatment IT: Intrathecal (lumbar puncture) IV: Intravenous (tail vein) IT HD 6 months 8 months3 months IT HD 1 month1 weekBirth 4.5 months IT LD pre-symptomatic early-symptomatic symptomatic premature death ✾IT HD + IV HD Combination therapy: Results with intrathecal route — While mice treated at a later stage in the disease with the lower dose did not show any significant benefits, treatment with this same dose extended lifespan and improved behavior for mice at earlier stages. — Treatment with a higher dose provided significant benefits in the early-symptomatic mice and greatly improved outcomes for younger mice. — We established that 1) early treatment is better; and 2) higher dose is better. — Although treating earlier is better, without newborn screening, the majority of INCL patients in the near future will be treated at the early-symptomatic or symptomatic stages. Intrathecal and intravenous dual treatment: Why combine both? — The IT dose is limited by the volume that can be safely injected into the intrathecal space. By combining it with an intravenous (IV) dose, we hypothesized that it could further improve survival and behavior in early-symptomatic mice. Results with combination therapy — The dual treatment provided significant benefits in behavior and survival over the intrathecal route alone in early- symptomatic mice. — We continue evaluating this cohort (with some of them currently reaching 16.3 months of age). — We are further exploring combination treatment in younger mice. IT HD IT LD IT HD IT LDIT HD IT LD