Michigan State University – Margaret Z. Jones, M.D., Final Report, September, 2001
Mucopolysaccharidosis IIID. Pathogenesis and Therapy research program relocated to the Medical College of Georgia and the University of Georgia from Michigan State University with the help of The Children’s Medical Research Foundation funding.
More than a decade ago, a goat kid with a severe neurological disorder was brought to me as a neuropathologist and Principle Investigator of a caprine lysosomal storage disease (LSD) associated with early neurodegeneration. Clearly, the goat kid did not have the previously undisclosed LSD (beta-mannosidosis) identified in my laboratory, but several years of research and collaborations revealed that the disabled kids LSD was the rarest of the Sanfilippo syndromes, type D. An animal model with lesions closely resembling those in human patients with the Sanfilippo syndromes had presented itself for the study of the pathogenesis and therapies of this devastating inherited disorder.
What has been learned as the decade of research at Michigan State University comes to a close with relocation of the goat colonies to the University of Georgia, the direction of the research program to the Medical College of Georgia and my relocation to the University of Michigan Department of Pathology as Consulting Nuropathologist?
First, a generous helping of serendipity as well as the good will and enthusiasm of scientists, clinicians and lay persons across the world enabled the identification of the biochemical defect as a deficiency of N-acetylglucosamine 6 sulfatase (6S) (Thompson et al 1992). Dr. John Hopwood made the human 6S cDNA probe available and Dr. Anson and I used this 6S probe to retrieve the goat cDNA. While the molecular basis of caprine MPS IIID was established and a DNA-based mutation analysis test was developed in my laboratory for the detection of MPS IIID and colony management (Friderici et al 1995; Cavanagh et al., 1995; Leipprandt et al, 1995), the recombinant 6S (r6S) enzyme was produced in John Hopwood’s laboratory ( Litjen et al 1997). Lesions in the brain and other tissues of two human patients affected with MPS IIID, studied for the first time by a team of international collaborators and me, revealed the striking similarity of the human and caprine forms of MPS IIID (Jones et al 1997, 1998; Alroy et al 1997). This included the primary accumulation of heparan sulfate glycosaminoglycans and the secondary accumulation of neutral and acidic glycolipids beginning prenatally (Liour et al.2001). Use of the mutation analysis test not only revealed a high carrier rate among the herds of Michigan Nubian goats but also enabled detection and purchase of a ready-made breeding colony (Hoard et al 1998). Sufficient r6S was available for in vivo studies of its uptake and distribution (Jones et al 1998); its efficacy, determined in a single affected goat, was restricted to depletion of accumulated HS-GAGs in non-neural sites (Downs-Kelly et al 2000). Therapies to reverse or ameliorate the progression of LSDs associated with early neurodegeneration in utero were developed in this large animal model.
One therapeutic approach was based on the potential efficacy of prenatally administered hematopoietic stem cells HSC as sources of native or r6S. Although HSCs did not engraft successfully as they do in other species, the techniques were established for safe ultra-sound-guided administration of HSCs to the prenatal animal. Further investigations are necessary to establish the conditions for HSC engraftment and the efficacy of this approach as a therapy for LSDs. The second approach to prenatal therapy utilized a murine CNS progenitor cell line established by Dr. Evan Snyder. When administered prenatally into the ventricular system of the brain, Drs. Mitchell-Herpolsheimer and Lovell and others demonstrated that these cells migrated throughout the cerebral hemispheres and brain stem and were well positioned to secrete enzyme for uptake. These promising studies will be continued under the direction of Dr. Stacey Kraemer in Dr. Robert Yu’s laboratory at the Medical College of Georgia and Dr. Paige Carmichael at the University of Georgia (see article Augusta Chronicle (http://www.augustachronicle.com/stories/071501/met_071-6307,000.shtml) while collaborators and I finalize the developmental profile of MPS IIID.
For information related to caprine MPS IIID, please contact Dr. Stacey Kraemer. Cells and/or semen from the MPS IIID goats have been relocated to benefit future research on Sanfilippo syndromes. Inquires can be made regarding their availability to Dr. Mark Haskins (U. Pennsylvania) and Dr. Esmail Zanjani (U. Nevada, Reno). I can be reached by e-mail – firstname.lastname@example.org. My thanks The Children’s Medical Research Foundation, MSU intramural funding sources, collaborating laboratories, the NIH, Michigan goat owners and parents of patients with Sanfilippo syndrome for their encouragement and contributions.
A list of all references available upon request from the Foundation.