Scientists from UB’s Hunter James Kelly Research Institute are making strides towards finding a treatment for Krabbe disease, an inherited fatal disorder affecting newborns. Their work was published this week in Neuron.
Lawrence Wrabetz and Laura Feltri are neuroscientists recruited to join HJKRI through Hunter’s Hope Foundation, established by Buffalo Bills Hall-of-Famer Jim Kelly following the death of his 8 year old son due to Krabbe leukodystrophy. Both experts specialize in myelination techniques that may benefit those suffering from diseases like multiple sclerosis or stroke.
Myelin
Myelin is the protective sheath surrounding axons in both the central and peripheral nervous systems, playing an essential role in nerve impulse conductance between cells in these systems. Damage to myelin may result in neurological disorders, including muscular weakness and numbness as well as memory problems; research studies are currently investigating its functions further.
Myelin is a unique combination of lipids and proteins. Basic proteins and proteolipid protein, or PLP, make up 60 to 80% of myelin protein content across most species; both types are readily soluble in sodium dodecyl sulfate (SDS) solution and distinguish themselves in polyacrylamide gel electrophoresis analyses to reveal their relative molecular weights.
PLP is an electrostatically held protein with positively charged domains held together by electrostatic interactions with negatively charged phospholipid headgroups found within adjacent bilayer phosphates, tightening and providing structure for tight membranes. PLP molecules also interact with myelin-associated glycoprotein and myelin basic protein-amyloid precursor protein to form an intracellular complex thought to aid myelin formation.
Myelin contains other proteins such as carbonic anhydrase, which may play a role in clearing away carbon dioxide from metabolically active axons; 5′-nucleotidase activity associated with monovalent cation transport; and Na,K-ATPase that may play an essential role in transport of ions into and out of myelinated axons. An additional double band with an approximate molecular weight of 50,000 can also be detected on electrophoretic patterns of myelin proteins; this double band has been identified as 2′:3′-cyclic nucleotide-3′-phosphodiesterase which likely constitutes several percent of myelin protein.
Myelin is enveloped by a unique mixture of lipids, consisting primarily of cholesterol and ethanolamine-containing plasmalogens. Studies have demonstrated that these lipids tightly bind myelin proteins and confer its characteristic properties on its membrane. Myelin also boasts an abundance of polyphosphoinositides; triphosphoinositide accounts for 4-6% of its phosphorus while diphosphoinositides represent around 1.5%. These characteristics make myelin unique among its sheaths! This special combination suggests its metabolism has unique properties as well.
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) is a progressive neurodegenerative condition of the peripheral nervous system affecting 1 out of 2,500 individuals and manifesting in weakness and deformities in feet. Although its exact cause remains unknown, many believe that CMT may be hereditary; men and women alike can be affected by it, though CMT Type 1A seems most prevalent (duplication of genes on Chromome 17 being one cause); other variants include 2A and 3A forms.
This progressive disorder often begins in childhood and becomes worse over time, impacting both motor and sensory nerves, often resulting in painful rigid foot deformities like pes cavus. Pain in the foot can lead to loss of balance and poor gait; weakening muscles of the foot also plays a part, impacting quality of life significantly.
CMT is a progressive neurodegenerative condition that typically begins in the feet and advances slowly upwards through the body. There are various treatment options available, including surgery and orthotics. Therapy’s goal is to slow its progress while restoring balance; foot orthotics may help patients walk better while decreasing risks of falling that often accompany this disorder.
Ankle-foot orthoses are the go-to therapy for CMT. However, adding dynamic plantar pressure devices into treatment can make a major difference – measuring foot function, pain levels and plantar pressure distribution during walking is monitored via these devices and fed back for feedback purposes – improving compliance with orthoses while decreasing visits to physiatrists.
Monitor foot and ankle strength in children with CMT by employing both manual tests and biomechanical analyses. According to one study, lack of ankle dorsiflexion was one of the main contributors to foot weakness and deformity caused by CMT, while in healthy preschool-age children ankle dorsiflexion is one of the strongest independent correlates of foot strength; its presence among CMT children could exacerbate gait abnormalities leading to a worsened course of disease.
Krabbe Disease
Jim and Jill Kelly established The Foundation after their son Hunter passed away from Krabbe disease at eight years old in 2005. Researchers from UB Hunter James Kelly Research Institute recently published a paper in Neuron that clarifies certain cellular mechanisms related to Krabbe Disease; their results could lead to improved outcomes for those living with it.
Researchers from University at Buffalo (UB) have discovered that mechanical forces play an essential role in myelin’s formation – the protective coating surrounding brain nerve fibers essential to nervous system health and essential for its normal function. Their work, published June 6 in Nature Neuroscience, may open the way to therapies targeting disorders affecting myelination.
Researchers studied oligodendrocytes, which produce myelin, and found they depended on certain calcium channels to activate them and myelination is controlled by them and their signals. Mice carrying genetic mutations that inhibit these channels demonstrated how their absence caused myelination defects.
These findings indicate that myelination defects associated with globoid cell leukodystrophy and other myelination diseases could potentially be addressed through blocking calcium channels with drugs or genetic therapy, thus providing insight into oligodendrocyte activation processes necessary for myelination processes and beyond.
HJKRI researchers recently received a $2 Million grant from the National Institutes of Health to develop new approaches to Krabbe Disease, an inherited fatal neurological condition. Lawrence Wrabetz MD and M. Laura Feltri MD of the Hunter James Kelly Research Institute as co-directors, professors of biochemistry and neurology respectively at Jacobs School of Medicine and Biomedical Sciences; Daesung Shin PhD as research assistant professor from Biochemistry department are leading this initiative.
Research funded over five years by this grant seeks to identify and target specific pathways that regulate myelination, with the ultimate aim of creating new therapeutics to improve outcomes for hereditary motor neuropathy (CMT), Krabbe disease, as well as other myelin-related conditions.
Bone Marrow Transplantation
Bone marrow transplant (also known as stem cell transplantation) introduces healthy blood-forming cells into a patient’s body to replace damaged ones caused by chemotherapy, radiation therapy or genetic diseases such as leukemia. Bone marrow may come from another donor (allogeneic transplant) or directly from them (autologous transplant), with this procedure performed when other therapies fail or a disease resurfaces after having undergone treatment.
Bone marrow transplantation can take anywhere from weeks to months and is a complex medical procedure requiring close monitoring in both an inpatient and outpatient setting. Patients may require transfusions of red blood cells and platelets during this process; additionally, any transplanted bone marrow must settle and produce normal blood cells within its new organ before it can be considered a success – a process called “engraftment”.
Before the transplant procedure begins, patients must go through a series of preparation measures in order to prepare the body for its new bone marrow. This involves taking medications which reduce body’s reactions to transplanted marrow and help avoid complications like infection after transplanting it into their bodies.
Hair restoration procedures may cause side effects such as hair loss, fatigue, nausea and mouth sores. Our care teams will discuss these risks with you in detail before helping to determine whether their benefits outweigh potential side effects.
Depending on your condition, our team of specialists may design an individualized treatment plan tailored specifically to you. These specialists may include a bone marrow transplant nurse coordinator, social workers to help navigate family and financial matters, dietitians who ensure adequate nutrition intake and physical therapists who will help rebuild strength.
When searching for donors with matching tissue types for transplant, our team searches both national and international registries to locate potential marrow donors with matching antigens on white blood cells (leukocytes). The more leukocytes match, the better chance there is of successful engraftment; when possible sibling donors may be preferred as this helps reduce complications that could arise during transplant.