In this Chapter…

• New Drugs

• Trophic Factors

• Engineered Antibodies

• Small Molecules and RNAs

• Cell and Gene Therapy

New Drugs

• Most medications today are developed using trial-and-error

• The potency of the agent can be determined by how well it attaches to the receptor/protein target in a test tube

• Candidates for new neurological drugs include

  • trophic factors

  • antibodies engineered to modify the interactions and toxicity of misfolded proteins

  • RNAi: interfering RNAs

    • They could reduce the toxic levels of individual proteins

  • Stem cells

    • They could replace dead or dying neurons

Trophic Factors

• Trophic factors control the development and survival of specific groups of neurons

• Once specific actions of these molecules and their receptors are identified, their genes can be cloned

  • Procedures can be developed to modify trophic factor-regulated functions in ways that might be useful in the treatment of neurological disorders

• NGF (Nerve Growth Factor): a trophic factor that slows the destruction of neurons that use acetylcholine

  • A possible treatment

  • Prevented cell death & stimulated regeneration & sprouting of damaged neurons that are known to die in Alzheimer’s disease

  • Holds promise for slowing memory deficits associated with aging

• Neutralizing molecules that stop or inhibit growth can help repair damaged nerve fiber tracts in the spinal cord

  • Antibodies that override the effect of Nogo-A helped some nerves of damaged spinal cords to regrow

    • Nogo-A: a protein that inhibits nerve regeneration

Engineered Antibodies

• We can “trick” the immune system into attacking proteins that cause neurological disease by vaccinating against them

  • There’s a risk of increased inflammation when the brain reacts to antibodies against its proteins

• A new approach is to engineer fragments of antibodies that can bind to and alter disease characteristics of specific proteins

  • These have produced promising results for Huntington’s, Parkinson’s, Alzheimer’s, and prion diseases

• Fruit flies that have been modified to carry a mutant gene for Huntington’s are generally too weak & uncoordinated to break out of their pupal case

  • When treated to also express a gene for anti-HD antibodies, all emerge as young adults

  • Treated flies live longer than untreated ones that manage to emerge and show less pathology in their brains

Small Molecules and RNAs

• Small-molecule drug candidates can be tested using high-throughput screening

• Many neurological diseases involve denatured proteins

• Lasers are used to measure whether proteins are clumped inside cells that have been distributed into containers with small molecules

  • They scan containers and report whether particular drugs have changed protein clumping

• Many diseases also involve the accumulation of abnormal proteins

  • If cells made fewer such proteins, the disease would slow down

• A new class of drugs involves removing the RNAs that code for these proteins

Cell and Gene Therapy

• Neuronal stem cells- unspecialized cells that give rise to cells with specific functions

• Neuronal stem cells can continuously produce all 3 cell types present in the brain:

  • Neurons

  • Astrocytes- glial cells that protect and nourish neurons

  • Oligodendrocytes- glial cells that surround axons and make the myelin sheath

• Viruses may be able to carry therapeutic genes into the brain to correct central nervous system diseases