The future for treating kids

John Grigg

Treatment

• What are the advances that are being implemented in the clinic now?

• What treatments are in research in preparation for clinical use?

Treatment

• Advances in the management pathway – Making the diagnosis – Assessing for systemic associations – Assessing and examining family members

Advances in diagnosis and imaging technologies

• Optical Coherence tomography (OCT)

Wide field imaging

Management of child with poor vision

• Optimise vision – Appropriate glasses – Medical therapy – Surgical interventions

Bioptic glasses • Bioptic glasses

– Miniature telescopes mounted on glasses

– If good peripheral vision can help people drive

– Good results for Stargardt retinal dystrophy patients

– Low vision clinics offer this. • UNSW school of Optometry

work with us on this

Management of child with poor vision

• Appropriate support services – Vision Australia – RIDBC – Guide Dogs – Teachers – Support groups

Future treatment

• Developmental eye conditions • Retinal Dystrophies • Inflammatory Eye conditions

Future treatment • Developmental eye

conditions – Childhood Cataracts – Childhood glaucoma – Microphthalmia

(small eye) – Aniridia

Future Treatments

• Retinal dystrophies and degenerations – Retinitis Pigmentosa – Lebers congenital

amaurosis – Stargardts disease – Choroideremia – Cone dystrophy

Future treatments • Inflammatory eye

conditions –Juvenile idiopathic

arthritis associated uveitis

–Infections inside eye.

Future treatments

• Gene therapy • Stem cell therapy • Bionic Eye • Biologic medicines • Advances in surgical procedures • Combinations of these

Gene therapy • Gene therapy approaches:

– Replacing a mutated gene that causes disease with a healthy copy of the gene

– Inactivating, or “knocking out,” a mutated gene that is functioning improperly

• gene cannot be directly inserted into a person’s cell – It must be delivered to the cell using a carrier,

or vector. – Viruses specially modified to carry DNA

Gene therapy the challenges

Progress in Retinal & Eye Research. 32:22-47, 2013 Jan.

Genes involved in photoreceptor function Mutations in these genes lead to retinal dysfunction

Current Gene therapy trials

• Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis RPE 65 mutations

• Gene replacement clinical trial for choroideremia (CHM)

• Study of Usher Patients Type 1B (MYO7A gene) targeting the Retinitis Pigmentosa component

• Source ClinicalTrials.gov U.S. National Institutes of Health

Gene therapy

• Gene therapy approaches are most suitable for treating disorders before the degenerative process has resulted in extensive retinal cell loss

Stem Cell therapies

• Stem cell (SC) therapy is an approach that seeks to repair and replace non-functioning neuro-retinal cells

• Stem cells are: – cells that can proliferate indefinitely – pluripotent thereby having the potential to

become any cell type when exposed to the appropriate stimuli and environment.

Proposed Mechanisms of Action • Stem cell transplant

–mediate cell survival via secretion of neuro-trophic factors

–transplanted cells act in a supportive or neuro-protective role.

• Embryonic stem cell (ESC) • Induced pluripotent stem cells (iPS cells)

Ong JM, da Cruz L. A review and update on the current status of stem cell therapy and the retina. Br Med Bull. 2012 Jun;102:133-46.

Stem cells and Growth factors CNTF clinical trial

• Ciliary neurotrophic factor (CNTF) • Pellet containing stem cells that secrete CNTF • Implanted in eye • Current trials

– Macular Telangiectasia at SSI – Achromatopsia USA NEI – Not effective in retinitis pigmentosa

Stem cells • Embryonic stem cells (ESCs) have the potential to

generate every cell type. • The use of human ESCs presents ethical issues

– because they are derived from human embryos – technical challenges with regard to tissue matching for

transplantation. • Induced pluripotent stem (iPS) cells are pluripotent

cells produced from adult somatic cells by overexpression of key transcription factors.

• Use of human iPS cells allows the generation of patient-specific cell lines.

Retinal stem cell therapy strategies

Bull ND, Martin KR. Concise review: toward stem cell-based therapies for retinal neurodegenerative diseases. Stem Cells. 2011 Aug;29(8):1170-5.

Bionic Eye • Bionic vision system – a camera – attached to a pair of glasses – transmits high-frequency radio

signals to a microchip implanted in the retina

– Electrodes on the implanted chip convert these signals into electrical impulses to stimulate cells in the retina that connect to the optic nerve

– Impulses passed along the optic nerve to the vision processing centres of the brain, where they are interpreted as an image

Bionic Vision system requirements

• Functional visual pathway – retina to the brain along the optic nerve

• some intact retinal cells

http://bionicvision.org.au/eye/prototypes/high_acuity

Bionic Eye • The electrode array determines the visual

potential. • To date 3 patients implanted in Australia with 24

electrode array. – One patient perceives light flashes. – One infection requiring removal

• Next generation working on 1000 electrode array chips.

• SSI retinal surgeons working with UNSW in sheep trials

3D printing and biology

• cells derived from the mature eye, were printed using a piezoelectric inkjet printer.

• preliminary and much more work is still required

B. Lorber, W-Ki Hsiao, IM Hutchings, KR Martin. Adult rat retinal ganglion cells and glia can be printed by piezoelectric inkjet printing.Biofabrication, 2014; 6 (1)

• “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents finally die, and a new generation grows up that is familiar with it. " -Max Planck

CNTF clinical trial

Retinal structure overview

European Journal of Pediatrics. 171(5):757-65, 2012

Stem Cell therapies

• Embryonic stem cell (ESC) • Induced pluripotent stem cells (iPS cells)

Stem cell clinical trials

• Safety and Tolerability of Sub-retinal Transplantation of Human Embryonic Stem Cell Derived Retinal Pigmented Epithelial (hESC-RPE) Cells in Patients With Stargardt Macular Dystrophy (SMD)