Investigators in the Heritable Disorders Branch (HDB) seek to understand the biochemical and molecular mechanisms of heritable disorders and to apply this information to the treatment of affected children.

Joan Marini’s group focuses on osteogenesis imperfecta, also known as brittle bone disease. The group is engaged in parallel treatment trials of bisphosphonate drugs in mice and children with OI. The murine study uses the Brtl mouse model for OI that was developed in the HDB; the model will allow direct determination of physical properties and biomechanics of OI bone. The laboratory has provided the first quantitation of the burden of mutant osteoblasts that is compatible with normal skeletal functioning in OI mosaics. The resultant information sets the target levels for cell therapy of dominant disorders of the skeleton at 50 to 60 percent

Forbes Porter’s group studies inborn errors of cholesterol synthesis, including Smith-Lemli-Opitz syndrome (SLOS). Using gene targeting in murine embryonic stem cells, the research team has produced three SLOS mouse models, including a null mutation and two hypomorphic point mutations. The null pups have the biochemical features of SLOS and decreased glutamate response consistent with neurological dysfunction in SLOS, but they die on the first day of life. The hypomorphic mouse mutants are non-lethal and will allow studies of pathophysiology and potential therapeutic interventions. The research group has provided insight into the autistic and obsessive-compulsive traits of SLOS patients and elucidated the common occurrence of compensated adrenal insufficiency.

Janice Chou’s group investigates glycogen storage disorders, developing approaches to somatic gene therapy that target the integral membrane–associated G6Pase enzyme to the liver and kidney. Treatment of the GSD-Ia mice generated in this laboratory with adeno- and adeno-associated virus vector–mediated gene transfer corrects the murine disease for a year and provides a model that might be applied to patients to eliminate long-term disease complications. Investigations of GSD-Ib, caused by defects in G6P transporter, have focused on mutation analysis. Most mutations completely abolish the transporter, but about a third have residual activity.

Anil Mukherjee’s group focuses on several genes, including palmitoyl-protein thioesterase and neutral ceramidase. Inactivating mutations in the PPT gene cause infantile neuronal ceroid lipofuscinosis (INCL), a severe neurodegenerative disease of childhood with no effective treatment. Using a Bench to Bedside Award, the group has initiated a pilot study to determine whether Cystagon is beneficial for INCL patients. Cystagon has virtually eliminated the ceroid deposition in white blood cell lysosomes of these patients, and an evaluation of the effect of treatment on neural degeneration of affected children is in progress.

A group led by Ida Owens investigates the mammalian UDP-glucuronosyltransferase (UGT) isozymes, which are critical for detoxifying endogenous and ingested toxins by conjugation with glucuronic acid. The research team has demonstrated that transient inhibition of gastrointestinal UGT activity markedly improves mycophenolic acid immunosuppressant activity. The team’s work has yielded a potential model for increasing the bioavailability of highly glucuronidated drugs. Studies combining in situ and biochemical analyses found that the enzymes were segmentally distributed throughout the GI in mucosal epithelia.