Structural Biochemistry/Elizabeth F. Neufeld
Elizabeth Neufeld is most notable for her work in advances in treatment for genetically inherited diseases such as Hurler's, Hunter's, and Sanfilippo syndrome. She was born in Paris and later moved with her family to New York in 1940. She was a research assistant for Elizabeth Russell at Jackson Memorial Laboratory, and shortly attended the University of Rochester for her masters until her father passed a way. After getting married she found a technician position available in the department of biology at Johns Hopkins. She later enrolled in the graduate program at UC Berkeley in Comparative Biochemistry.
As her career developed she eventually studied Hurler's syndrome, an autosomal recessive inherited disease resulting in a multitude of effects including progressive mental retardation and leading to death by about age 10. The biological problem that occurs in those with Hurler's syndrome was known to be associated with the storage and excretion of mucopolysaccharides, though the specifics had yet to be determined. Patients fibroblasts, synthesizing cells found in connective tissue, showed irregular accumulation of mucopolysaccharides. At first Neufeld thought it to be a problem of overproduction, though her experiments revealed that it was in fact a result of insufficient degradation.
After Danes and Bearn published a paper postulating that normal cells assist mutant cells with mucopolysaccharide degradation, Neufeld's partner had a mix up in Hunter's and Hurler's cells in the lab. Keeping this plate with the mixed cells, he and Neufeld discovered that the cells in fact underwent some normalization! The cells appeared to be secreting 'corrective factors' in mixtures of different genotypes. The corrective factor was found to be α-L-iduronidase. Hurler factor has α-L-iduronidase activity, but it is deficient. While Neufeld's group was looking for the uptake signal, a researched named Sly found that mannose-6-phosphate was the recognition signal for lysosomal enzymes while studying a disease with β-glucuronidase deficiency--another mucopolysaccharide storage disease.
With these key pieces of knowledge, Neufeld and fellow researches sought therapy for those with Hurler's syndrome. Meanwhile, Robert Shull who found signs of lysosomal storage diseases in a Plott hound, sent Neufeld fibroblasts which ended up being α-L-iduronidase deficient. Shull then started a colony of this dog to understand more about this disease, and created an animal model for enzyme replacement therapy. Using cDNA of α-L-iduronidase, Neufeld teamed up with Emil Kakkis and used Chinese hamster ovary cells to make recombinant human and canine DNA, which successfully excreted the enzyme with the M6P signal and was highly corrective! This cDNA was used in α-L-iduronidase deficient dogs and found to be effective! After short and long term trials with dogs, then 55 human trials, the FDA approved the treatment in 2003 for Hurler's syndrome. It was later approved for other mucopolysaccharide storage diseases.
Neufeld spent 35 years of her life developing a treatment for the rare lysosomal enzyme disease. Thanks to her, enzyme replacement therapy for alpha-L-Iduronidase deficiency is now an acceptable treatment. Using the mannose 6-phosphate system, the therapy is now being used to treat Hunter and the Maroteaux-Lamy syndromes.
Despite the acceptability of enzyme replacement therapy, there are still many issues. One major issue is that this is a highly expensive treatment, both for administration, and for further research. Another major restriction in this treatment is that not all of the human body is equally receptive to the new enzymes. For example, especially in the central system, intravenously injected enzymes are blocked by the blood-brain barrier. This is rather unfortunate as many patients with mucopolysaccharide storage diseases have neurologic variations. Though research has been done for alternative administration methods, and other possible pharmaceuticals to correct the enzyme misfolding, as of right now, only the alternative administrations have been brought to clinical trials. Thus it may be many years before the problem is fully solved.
Tranplantation of hematopoietic stem cells from bone marrow or cord blood may be another therapy for Hurler syndrome, but it is still a risky procedure. Additionally, it is thought that there might be a "takeover" with the donor's cells gradually replacing the patient's cells.
Since her successful efforts in therapy for Hurler's syndrome, Neufeld has received the Javits Award for her work on Tay-Sachs disease, and is now interested in Sanfiippo Syndrome. Each type of Sanfilippo syndrome has a lysosomal enzyme deficiency, and Neufeld discovered the syndrome to be a tauopathic disease-- a group of neurodegenerative diseases which all lead to dementia. She found that the expression of many mRNAs changed in the experiments, the mRNA encoding lysozyme stood out as it was elevated over 6 times the normal in both the affected and control areas in MPS IIIB mice. Immunohistochemistry demonstrated that the lysozyme protein was elevated only in the medial entorhinal cortex. Lysozymes have been studied for a long time, and in fact was one of the first enzymes to be studied, and was discovered to be a product of phagocytes an epithelial cells by Alexander Fleming. However, it had not yet been described in neurons. Neufeld proposed that the elevated levels of the lysozyme in the medial entorhinal cortex could induce hyperphosphorylated tau.
Neufeld hopes that research into Alzheimer's (another disease in the tauopathy family) will also lead to advancements in understanding and treating Sanfilippo Syndrome.
Annu. Rev. Biochem. 2011.80:1-15. Download from www.annualreviews.org by University of California - San Diego on 11/10/11. For personal use only.