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Conference Report

Bethesda Marriott, Bethesda, MD
October 22-24, 2006

Organization
Rationale and Goals
Conference Summary
Agenda
Participants

Organization

Sponsored by: National Institute of Neurological Disorders and Stroke (NINDS) and the Juvenile Diabetes Research Foundation (JDRF)

Chair: Steven Scherer (University of Pennsylvania)

Organizing Committee: Steven Scherer (University of Pennsylvania), Gary Bennett (McGill University), Eva Feldman (University of Michigan), Jack Griffin (Johns Hopkins University), Michael Shy (Wayne State University), and John Porter (NINDS)

Rationale and Goals

The NIH Peripheral Neuropathy Conference was designed to examine the status of research in the peripheral neuropathies with the additional goal of optimizing the development of new therapeutics. The organization of research and funding by the presumed etiology of the neuropathy (inherited, diabetic, inflammatory, or toxic) has tended to fragment the field, diminishing the cross-talk between researchers who study different types of neuropathy. Rather than organizing around the types of peripheral neuropathy, which might reinforce existing fragmentation, this Conference took a novel approach designed to integrate concepts and researchers from different areas to facilitate coordination and collaboration across the various types of peripheral neuropathies, with the ultimate goal of facilitating the development of therapies.

Experts from basic and clinical science were recruited into Topic Groups to examine the phases of therapeutic development through pre-meeting activities and then to present consensus reports at the Conference. The Topic areas were: (a) identifying disease mechanisms to provide therapeutic targets, (b) examining the status of diagnosis and biomarkers, to ensure sufficiently sensitive diagnostics to detect peripheral neuropathy at an early enough stage to make therapeutics effective, to adequately stratify patients for clinical trials, and to provide effective surrogates to evaluate intervention efficacy in clinical trials, (c) examining the status of therapeutic development efforts leading to Investigational New Drug (IND) applications to the FDA, and (d) developing protocols, common data elements, endpoints, and infrastructure to facilitate the conduct and cross-comparison of clinical trials. The Conference outcomes consist of status reports on disease mechanisms in the axonal neuropathies, demyelinating neuropathies, and neuropathic pain, diagnostics and biomarkers, therapeutic development, and clinical trials, including specific recommendations for the way forward in achieving safe and effective therapies for the peripheral neuropathies. The ultimate goal is that this Conference initiates dialog to reduce the fragmentation, and increases collaborations and awareness of complementary strengths for the often less glamorous but absolutely essential activities that are required to bring new therapies to patients suffering with the burden of peripheral neuropathy.

Conference Summary

A. Prelude
B. The Structure and Function of Peripheral Nerves
C. Causes and Classifications of Peripheral Neuropathy
D. Disease Mechanisms: Axonal Neuropathies
E. Disease Mechanisms: Demyelinating Neuropathies
F. Disease Mechanisms: Neuropathic Pain
G. Diagnosis and Biomarkers
H. Therapeutic Development
I. Clinical Trials

A. Prelude

The development of novel therapeutics for the peripheral neuropathies will require a change in mindset and behavior among academic researchers, from hypothesis-driven to goal- or milestone-driven approaches, a change in collaboration paradigms, bringing in the broader range of expertise needed for development, production, and commercialization of new drug or biologic therapeutics, and a change in funding paradigms, since no single advocacy organization, corporation, or governmental agency can support the full gamut of activities required for therapy development in rare diseases. The problem facing the peripheral neuropathy field is that there are few effective therapies and substantial corporate involvement is currently restricted to limited areas (e.g., neuropathic pain). For new therapies to be developed, academic researchers will need to broaden their perspective about what is needed to bring new drugs and biologics to clinical trials. Such efforts will lower the scientific, corporate, and regulatory risks and facilitate corporate interest in therapy development programs for the peripheral neuropathies, many of which are rare diseases not readily embraced by corporate structure. For peripheral neuropathies, there is well-founded optimism that many of the corporate keys to program success either have been or can be met:

• Disease amenable to palliative or curative therapy;
• Chronic diseases more tractable than acute;
• Therapeutic linked to a validated disease mechanism;
• Patients readily diagnosed at a sufficiently early stage of disease (and existence of markers for patient stratification and surrogate endpoints);
• Clinical trials feasible in the target population;
• Ensure that therapeutic traits are optimized by program design.

Furthermore, studying individual kinds of peripheral neuropathies may provide answers that are more generally applicable, as well as additional benefits such as reducing the duplication of effort and increasing the likelihood that specific therapies will be developed.

This Conference took the first step of bringing together academic researchers on October 22-24, 2006 to begin to assess what knowledge and tools are available and what is still needed to develop novel therapeutics in this field-a key goal was to assess the current status of research in this area and begin the change of mindset and behavior that is necessary to therapy development. Representatives of the major funding agencies-patient advocacy organizations and components of the NIH-also participated. The NINDS and JDRF have initiated programs that address the iterative steps needed for an FDA IND application for therapeutics in peripheral neuropathy, thereby addressing the necessary change in funding paradigms to support a type of research not supported by traditional, hypothesis-driven grant programs. The NINDS funding program for therapeutic development is described at: http://www.ninds.nih.gov/funding/research/translational/index.htm and the JDRF program is described at: http://www.jdrf.org/.

The next steps must include a change in collaboration paradigms, which will require another level of interaction to obtain input from biotechnology companies, large pharmaceutical companies, regulatory agencies, and experts in development of academic-corporate partnerships. Finally, patient resources, expertise in translational research, and funding are scare commodities. From experience in other diseases, it will be essential to value team versus individual approaches (crossing academic, corporate, and national boundaries to collaborate and share knowledge and resources) in order to achieve success in moving any drug or biologic into the clinic.

B. The Structure and Function of Peripheral Nerves

The peripheral nervous system (PNS) is composed of motor, sensory, autonomic, and enteric neurons, as well as the glial cells that ensheathe their axons (Schwann cells) and cell bodies (satellite cells). Motor neurons innervate skeletal muscle fibers; autonomic (sympathetic and parasympathetic) neurons innervate and regulate the function of smooth muscle and secretory cells in a wide number of tissues. Sensory neurons innervate a variety of specialized sensory appendages (e.g., muscle spindles, Golgi tendon organs, Pacinian corpuscles, Ruffini corpuscles, hair follicles, touch domes) or terminate in anatomically unspecified nerve endings; each kind has precise patterns of synaptic connections in the central nervous system. In addition to their anatomical and physiological specifications, different kinds of neurons require different trophic factors for their development and perhaps even their maintenance.

The peripheral nerves themselves are largely comprised of myelinated and unmyelinated axons, typically grouped in fascicles, each of which is surrounded by a cellular barrier, the perineurium. Myelinated axons range from 1 to 10 microns in diameter. Alpha motor axons and a subset of sensory axons (Ia afferents) are the largest; most of the intermediate and smaller myelinated axons are sensory. Unmyelinated axons (C fibers) are smaller yet (typically less than 1 micron in diameter); these are autonomic and sensory axons, including those subserving nociception. Multiple unmyelinated axons and their associated Schwann cells comprise Remak bundles.

In the electron microscope, the most obvious structures in axons are neurofilaments and bundles of microtubules. Neurofilaments regulate the axonal caliber, and are composed of three subunits, termed heavy, medium, and light. Microtubules are composed of tubulins, and form the scaffolds for kinesins and dynactin; the molecular motors for orthograde and retrograde axonal transport, respectively. In spite of their deceptively simple appearance in fixed material, imaging reveals that living axons are highly active, with mitochondria and vesicles in seemingly incessant motion. Because the cell body is the site of most protein synthesis, axonal proteins must traffic great distances. Similarly, signals originating from the nerve terminal or axon itself must travel the entire length of the axon to reach the cell body.

Myelin is a spiral of specialized cell membrane that ensheathes axons except for small gaps - the nodes of Ranvier. The myelin sheath itself can be divided into two domains - compact and non-compact myelin - each of which contains a non-overlapping set of proteins. Compact myelin forms the bulk of the myelin sheath; non-compact myelin is found in paranodes (the lateral borders of the myelin sheath) and in Schmidt-Lanterman incisures (the funnel-shaped interruptions in the compact myelin). Compact myelin is largely comprised of lipids, including specialized lipids and proteins that play essential roles. Non-compact myelin is distinguished by tight junctions, gap junctions, and adherens junctions, between the apposed cell membrane of the myelin sheath.

The function of peripheral nerves is to conduct action potentials. In unmyelinated axons, action potentials conduct continuously, and slowly, about 1 meter/second. In myelinated axons, action potentials jump from node to node; this is called saltatory conduction and is much faster (up to 80 meters/second) than continuous conduction. Myelin sheaths facilitate saltatory conduction by reducing the capacitance of the internode, and by organizing axonal ion channels. In the nodal region, molecular interactions between Schwann cell microvilli and the nodal axolemma cluster voltage-gated Na+ channels, which are the source of depolarizing current required for saltatory conduction.

C. Causes and Classifications of Peripheral Neuropathy

Any disease of peripheral nerves can be called peripheral neuropathy, or simply neuropathy. There are many causes, but all of them injure axons or myelinating Schwann cells. Clinically, this dichotomy is reflected in the common usage of the terms "axonal" or "demyelinating" as adjectives to characterize an individual patient's peripheral neuropathy. This dichotomy has its roots in the cellular and molecular biology of axons; the very specializations that make them unique make them vulnerable to diseases. In addition to the issue of whether they are axonal or demyelinating, neuropathies can be classified according to whether they are inherited or acquired, or part of a syndrome. Examples are shown in Table 1; some of these will be discussed later.

Table 1. Classifying causes of neuropathies.
Neuropathies are classified by whether they are inherited or acquired, part of a syndrome, and by their primary pathological cause (axonal or demyelinating). Examples of each are provided. Axonal neuropathies can be further subdivided according to whether they chiefly large myelinated axons and/or small unmyelinated axons (so-called "small fiber" neuropathies). A few axonal neuropathies differentially affect sensory and motor axons.

^aMLD: metachromatic leukodystrophy; FAP: familial amyloid polyneuropathy; GAN: giant axonal neuropathy; AIDP/CIDP: acute/chronic inflammatory demyelinating polyneuropathy; AMAN: acute motor axonal neuropathy.

The classification of non-syndromic inherited neuropathies is more elaborate. These are called Charcot-Marie-Tooth disease (CMT) or Hereditary Motor and Sensory Neuropathy (HMSN). Different kinds are recognized clinically, aided by electrophysiological testing of peripheral nerves. For dominantly inherited forms, if the forearm motor nerve conduction velocities (NCVs) are greater or less than 38 m/s, the neuropathy is traditionally considered to be axonal (CMT2/HMSN II) or demyelinating (CMT1/HMSN I), respectively, although "intermediate" forms have been recognized. CMT1 is more common, and nerve biopsies show segmental demyelination and remyelination as well as axonal loss. CMT2 typically has a later onset and is associated with loss of myelinated axons, without much demyelination. Whereas CMT1 and CMT2 are relatively common, dominantly inherited disorders, there are recessively inherited neuropathies; these are rarer, typically more severe, and the demyelinating forms are usually called CMT4. Besides CMT, other inherited neuropathies have been traditionally given different names. Hereditary neuropathy with liability to pressure palsies (HNPP) is a milder neuropathy and often has distinct episodes of focal neuropathies. Congenital hypomyelinating neuropathy and Dejerine-Sottas neuropathy are severe neuropathies (named according to whether they were clinically recognized around birth or during infancy, respectively); affected patients typically have NCVs less than 10 m/s, and dysmyelinated axons characterized by improperly formed myelin sheaths. In addition to these sensory and motor neuropathies, there are neuropathies that chiefly if not exclusively affect sensory or motor axons. Hereditary sensory and autonomic neuropathies are a group of disorders that affect sensory neurons and/or axons, with variably involvement of autonomic neurons/axons. Hereditary motor neuropathies are a group of disorders that chiefly affect motor axons, although some show a variable degree of CNS involvement.

Table 2. Non-syndromic inherited neuropathies (some may be neuronopathies).
Only the disorders in which the mutant gene has been identified are listed. For more discussion, see: http://www.ncbi.nlm.nih.gov/Omim, http://www.neuro.wustl.edu/neuromuscular/time/hmsn.html, and http://molgen-www.uia.ac.be/CMTMutations/DataSource/MutByGene.cfm.

 

HNA: hereditary neuralgic amyotrophy

Most of the symptoms (reported by patients) and signs (observations of clinicians) of neuropathy owe to a loss of function of the affected axons. Thus, loss of motor axons diminishes strength, loss of large myelinated sensory axons diminishes balance and vibratory sensation, loss of small myelinated and unmyelinated axons diminishes temperature and nociceptive sensation. In addition, spontaneous activity in affected axons may produce positive symptoms such as fasciculations (motor axons), paresthesias (myelinated sensory axons), and, most importantly, pain (unmyelinated axons).

D. Disease Mechanisms: Axonal Neuropathies

In many neuropathies, the clinical features tend to have a distal predilection, both in terms of first appearance and in ultimate severity. This suggests that axonal length is a factor in determining which neural elements are at risk. But distal distribution does not mean that the defect necessarily lies in the axon; it could just as well represent a primary neuron cell body abnormality. For instance, large doses of pyridoxine (vitamin B6) promptly kill large primary sensory neurons, whereas smaller doses cause only subtle shrinkage of these neurons and indolent, distal axonal degeneration. Thus, a modest neuronal abnormality may result in distal axonopathy, but a more severe insult of the same type may cause the neuron itself to degenerate as the primary event.

The selective vulnerability of PNS neurons that leads to neuropathy may be the axons themselves, whose length makes them the longest cells in the body. In addition, the volume of the axon is vastly greater than the cell body, which must synthesis its various molecular components and delivery them via axonal transport. The ability of several useful medications that affect microtubules - taxol, vincristine, and colchicine - to cause an axonal neuropathy may reflect their effects on axonal transport. Several other toxins, such as n-hexane and IDPN, cause a peripheral neuropathy that is characterized by massive accumulations of neurofilaments.

Hereditary axonal neuropathies also highlight the molecular vulnerability of axons. Dominant mutations in NEFL, the gene encoding the light subunit of neurofilament, cause an axonal neuropathy. Recessive mutations in the gene encoding gigaxonin cause giant axonal neuropathy, a syndrome affecting both PNS and CNS neurons. Gigaxonin binds to a microtubule-associated protein (MAP-1B-LC), and stabilizes microtubules, thereby promoting their axonal transport. A dominant mutation in the gene encoding kinesin KIF1Bb, which transports synaptic vesicles to the axon terminals, causes an inherited axonal neuropathy. A dominant mutation in the gene that encodes KIF5A likely causes a length-dependent axonal neuropathy of CNS axons, and thus a different clinical phenotype, hereditary spastic paraparesis. Finally, dominant mutations in p150Glued cause a length-dependent motor neuropathy with an unexplained predilection for the larynx and arms. p150Glued is a component of the dynactin/dynein complex - the motor for retrograde axonal transport.

In addition to disorders that affect the axonal cytoskeleton and axonal transport, other mutations that cause inherited axonal neuropathies underscore the importance of mitochondria. In particular, dominant mutations in MFN2, the gene that encodes mitofusin 2, are a common cause of CMT2. These mutations probably interfere with the ability of mitochondria to fuse, and possibly their ability to move. GDAP1 is also localized to mitochondria, and recessive mutations also cause peripheral neuropathy. Other syndromic mitochondrial diseases also cause neuropathy, and some of the spastic paraplegias are caused by mutations in genes