Ou Medicine

Muna I. Naash

Professor, Department of Cell Biology
Edith Kinney Gaylord Presidential Professor
Adjunct Professor of the Oklahoma Center for Neuroscience

EDUCATION

Ph.D., Biochemistry/Cell Biology, Baylor College of Medicine, Houston, Texas

BIOGRAPHY

Dr. Naash earned her Masters and Ph.D. in Biochemistry, the latter from Baylor College of Medicine.  Her post-doctoral fellowship was in the Department of Ophthalmology at Baylor College of Medicine in Houston.  She holds the Edith Kinney Gaylord Presidential Professorship in the Department of Cell Biology and is a former Director of the Cell Biology Graduate Program at OUHSC.  She also holds an Adjunct Faculty appointment in the Oklahoma Center for Neuroscience and the OUHSC Graduate College.  She is very well published and serves as a reviewer for study sections and journals.  She currently serves on study sections for the NIH and the Foundation Fighting Blindness.  Dr. Naash is currently funded by three R01 grants from the NIH/NEI, in addition to having funding from the OCAST, OCASCR and the Foundation Fighting Blindness.

RESEARCH SUMMARY

1. Photoreceptor-specific tetraspanin proteins in outer segment morphogenesis.  There are several ongoing research interests of my group.  One of our main interests is to understand the role of photoreceptor tetraspanin proteins [retinal degeneration slow (RDS) and rod outer segment membrane protein-1 (ROM-1] in the morphogenesis of the closed rim structures characteristic of rods in contrast to the open rim structures of cones.  This work has been funded by NIH since 1992.  We are interested in identifying RDS partners which contribute to the differential role of RDS in maintaining the outer segment (OS) structure in rods vs. cones.  Of particular interest are understanding the pathological mechanisms that underlie RDS-associated retinal dystrophies.  Without RDS, OSs are not formed, and over 100 different mutations in patients have been linked to several forms of inherited retinal diseases.  Proteomics, molecular biology, protein biochemistry, tissue culture, transgenics, knockout and knockin technologies are employed.  We are also investigating the effect of disease-causing mutations on RDS/ROM-1 complex formation and studying the processes that result in their targeting to the OS.

2. Nanoparticle-mediated ocular gene delivery and vector engineering.  Our second interest is to develop gene and stem cell therapies for eye disease, particularly diseases of the retina and retinal pigment epithelium (RPE).  The work is funded by two R01 grants from NIH to develop non-viral therapeutic interventions to combat loss of vision in models of ocular diseases.  The eye is outstandingly well suited for the development of novel therapeutic approaches.  It is easily accessible and allows local application of therapeutic agents with reduced risk of systemic effects.  We are using self-compacted DNA nanotechnology along with advanced vector engineering stragetgies to enhance gene expression levels and longevity of expression.  We are testing mini-circle vectors that lack bacterial backbone, self-replicating vectors, and several elements designed to prolong/improve expression, including S/MAR sequences, enhancers, insulators, and helper-independent Sleeping Beauty Trasposon-Transposase.  Nanoparticles (NPs) carrying these vectors are designed to deliver therapeutic genes specifically to the RPE or photoreceptors.  Historically, non-viral gene delivery options have been plagued by inefficient cellular uptake, silencing of gene expression, and occasionally induction of immune responses.  However, we have shown that our NPs are highly efficient in transfecting differentiated, post-mitotic cells and that they exhibit no signs of toxicity, even after repeated dosing to the eye.  We also show that these NPs drive long-term gene expression, and can mediate significant improvement in the retinal degenerative phenotype in several models of retinitis pigmentosa, Stargardt’s Macular Dystrophy and Leber’s Congenital Amaurosis (LCA).  A key distinguishing feature of these NPs is their large capacity and demonstrated comparable gene expression regardless of vector size (tested up to 20kb).  We have also demonstrated that NPs can drive retinal gene expression at levels on a scale comparable to AAVs.  Combined, these features make NPs an attractive option for the treatment of chronic monogenic ocular diseases.

3. Adult stem cell therapy for photoreceptors.  Cell transplantation represents a promising therapeutic avenue to combat neurodegenerative diseases.  Ocular diseases such as age related macular degeneration (AMD) and retinitis pigmentosa (RP) are prime candidates for such therapies.  These diseases are characterized by photoreceptor degeneration, and transplanted cells would have to be delivered precisely to the location where the degeneration is observed.  Although transplanted embryonic stem cells (ESCs) have been shown to effectively differentiate and integrate into various layers of the retina; it has been repeatedly demonstrated that they fail to differentiate into photoreceptor cells when transplanted into the adult retina.  In contrast, it has been shown that post-mitotic retinal progenitor cells (RPCs) extracted from post-natal mice were able to integrate into the outer nuclear layer (ONL) and mature into photoreceptors.  This has led us to ask, at what time point in development are cells primed to have neuro-regenerative capability?  If the time point/condition at which cells have maximal capacity for integration and differentiation can be determined, then steps can be taken to induce such a condition in vitro, prior to transplantation, with the goal of generating a renewable cell population capable of efficient integration and differentiation.  We propose to transplant e-GFP labeled RPCs into wild-type and mouse models of rod and cone degeneration.  We plan to track the localization, integration and differentiation of these cells in the host retina and examine retinal structure and function to detect improved phenotypes.  We also focused on maximizing integration of RPCs and evaluating the importance of the outer limiting membrane in this process.

PUBLICATIONS (Since 2010)

2. Conley, S. M., Stuck, M. and Naash, M. I. Electrophysiological characterization of rod and cone responses in the baboon non-human primate model. Adv Exp Med Biol. In Press.

3. Han Z, Conley S. and Naash MI. Gene therapy for Stargardt Disease associated with ABCA4 gene. Adv Exp Med Biol. In Press.

4. Koirala A, Conley S. and Naash MI Episomal maintenance of S/MAR-containing non-viral vectors for RPE-based diseases. Adv Exp Med Biol. In Press.

5. Han Z, Conley S, Makkia R, Cooper MJ, and Naash MI. (2012) Comparative analysis supporting DNA nanoparticles as an attractive complement to AAVs for ocular gene delivery.  PLOS ONE. In Press.

6. Chakraborty D, Rodgers KK, Conley SM, and Naash MI (2012) Structural characterization of the second intradiscal loop of the photoreceptor tetraspanin RDS. FEBS J. 2012 Nov 2. doi: 10.1111/febs.12055.

7. Han Z, Guo, J, Conley S, Makkia R, and Naash MI. (2012) Retinal angiogenesis in the Ins2^Akita mouse model of diabetic retinopathy.  Invest Ophthalmol Vis Sci. 2012 Dec 6. doi:pii: iovs.12-10959v1. 10.1167/iovs.12-10959.

8. Conley, S. M., and Naash, M. I. (2012) Gene-Based Medicine for Ocular Diseases, In Ocular Drug Delivery Systems (Thassu, D., and Chader, G. J., Eds.), pp 327-353, CRC Press, New York.

 9. Han Z, Conley S, Makkia R, Cooper MJ, and Naash MI. Nanoparticle-mediated ABCA4 delivery rescues the degenerative Stargardt’s phenotype. J Clin Invest. 2012 Sep 4;122(9):3221-6. PMID:22886305

10.  Sherry DM, Kanan Y Hamilton R, Hoffhines A, Arbogast KL, Fliesler SJ, Naash MI, Moore KL and Al-Ubaidi MR (2012) Differential developmental deficits in retinal function in the absence of either protein tyrosine sulfotransferase-1 or -2. PLoS One. 2012;7(6):e39702.

11.  Chakraborty, D., Conley, S.M., Nash, Z., Ding, X.Q., Naash, M.I. (2012) Overexpression of ROM-1 in Cone-dominant Retina. Adv Exp Med Biol. 2012;723:633-9. PMID:22183387

12.  Conley, S.M., Chakraborty, D., Naash, M.I. (2012) Mislocalization of oligomerization-incompetent RDS is associated with mislocalization of cone opsins and cone transducin. Adv Exp Med Biol. 2012;723:657-662. PMID:22183390

13.  Stuck M, Conley S, and Naash MI. (2012) Development of abnormal retinal lamination in the nrl^-/- mouse. PLoS One. 2012;7(3):e32484. Epub 2012 Mar 12. PMID:22427845

14.  Han Z, Koirala A, Makkia R, Cooper MJ, and Naash MI. (2012) Direct gene transfer with compacted DNA nanoparticles in retinal pigment epithelial cells: expression, repeat delivery and lack of toxicity. Nanomedicine (Lond). 2012 Apr;7(4):521-39. PMID:22356602

15.  Koirala A, Makkia RS, Cooper, MJ and Naash MI (2011) Nanoparticle-mediated gene transfer specific to retinal pigment epithelial cells. Biomaterials. 2011 Dec;32(35):9483-93. PMID: 21885113.

16.  Conley S, Cai X, Makkia R, Sparrow J, and Naash MI. (2011) Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt's dystrophy.  Biochim Biophys Acta. 2011 Oct 13. PMID:22033104

17.  Macdonald IM, Naash MI, Ayyagari R. (2011) Retinal degeneration: genetics, mechanisms, and therapies. J Ophthalmol. 2011;2011:764873. PMID:22132314

18.  Conley S, Stuck M, and Naash MI. (2011) Structural and Functional Relationship of Photoreceptor Tetraspanins with other Superfamily Members.  Cell Mol Life Sci. 2012;69(7):1035-47. PMID:21655915

19.  Han Z, Conley SM, and Naash MI. (2011) AAV and compacted DNA nanoparticles for the treatment of retinal disorders: challenges and future prospects.  Invest Ophthalmol Vis Sci. 10;52(6):3051-9. PMID:21558483

20.  Chakraborty D, Conley, S and Naash MI (2010) Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS. Hum Mol Genet. 19 (24):4799-812. PMID:20858597.

21.  Cai X, Cheng, T and Naash, MI. (2010) A 350 bp region of the proximal promoter of Rds drives cell-type specific gene expression. Exp Eye Res. Aug;91(2):186-94. PMID:20447394.

22.  Conley SM and Naash MI (2010) Nanoparticles for Retinal Gene Therapy. Prog Retin Eye Res. Sep;29(5):376-97 PMID:20452457.

23.  Conley SM., Ding X-Q, Naash MI (2010) RDS in Cones Does Not Interact with the Beta Subunit of the Cyclic Nucleotide Gated Channel. Adv Exp Med Biol. 664:63-70. PMID:20238003

24.  Chakraborty D, Conley S, Fliesler SJ, and Naash MI (2010) The Function of Oligomerization-Incompetent RDS in Rods. Adv Exp Med Biol. 664:39-46. PMID:20238000

25.  Cai X, Conley S and Naash, MI. (2010) Gene therapy in the retinal degeneration slow model of retinitis pigmentosa. Exp Med Biol. 664:611-9.

26.  Conley SM, Stricker, HM, Naash MI. (2010) Biochemical analysis of phenotypic diversity associated with mutations in codon 244 of the RDS gene. Biochemistry, 2010 Feb 9;49(5):905-11. PMID:20055437.

27.  Cai X, Conley SM, Nash Z, Fliesler SJ, Cooper MJ, Naash MI. (2010) Gene Delivery to Mitotic and Postmitotic Photoreceptors Via Compacted DNA Nanoparticles Provides Improved Phenotype in a Mouse Model of Retinitis Pigmentosa.  FASEB Journal. 24(4):1178-91. PMID:19952284.

MAILING ADDRESS

University of Oklahoma Health Sciences Center

Department of Cell Biology

P.O. Box 26901

Oklahoma City, OK 73126-0901

Phone: (405) 271-8001 ext. 47969

Fax: (405) 271-3548

Muna-Naash@ouhsc.edu