The Current State of Rett Research

The last few years has brought unprecedented attention to Rett Syndrome by academic scientists, researchers and executives of pharmaceutical and biotech companies and more recently, life sciences investors. The interest stems from the advantages enjoyed by the Rett field: a known and single genetic cause, expectation of reversibility, NIH funded natural history study and Rett clinics with significant patient populations.

The graphic below encapsulates the various approaches that are currently being pursued.

Since Rett Syndrome is caused by defective MECP2 it stands to reason that approaches that attack the root cause, MECP2 itself, hold the greatest promise of significantly improving symptoms. Therefore approaches such as activating the silent MECP2, gene therapy and protein replacement can be classified as potentially curative approaches.

On the other hand therapeutic interventions that are downstream of MeCP2 will likely improve a symptom or subset of symptoms. These approaches are treatments rather than cures.

Since 2008 RSRT has awarded $41 million to research.

Current Projects

Researchers Go Here

Chart of Treatments & Strategies

Table of Treatments

Therapies targeted at MECP2

Approach How it Works Investigators Advantages Potential Limitations
Gene Therapy Introduces a healthy MECP2 gene into cells

Gene Therapy Consortium (P) (Gail Mandel, Stuart Cobb, Steve Gray, Brian Kaspar)

James Eubanks (P)

Jean-Christophe Roux (P)

Attacks the underlying cause of Rett so has the potential to profoundly impact symptoms

Published animal studies show reversal of some symptoms in aged female mice.

Could result in too much MECP2 in cells that might be detrimental

Gene therapy must be brain penetrant and target large number of cells

No FDA approved gene therapy treatment exists yet in US so steeper regulatory pathway is likely

Activating MECP2 on the inactive X Chromosome Mechanism will likely be unique to each compound

Ben Philpot, Bryan Roth, Terry Magnuson (D)

Toni Bedalov, Marisa Bartolomei (D)

Jeannie Lee (D)

Rudolf Jaenisch (D)

Michael Green (D)
(trying to activate the entire X chromosome)

Attacks the underlying cause of Rett so has the potential to profoundly impact symptoms

Should not result in too much MECP2 so dosage should not be an issue

Drug must be brain penetrant and target a large number of cells

Potential for increased expression of other genes on the X chromosome

No robust candidates yet identified

Translation Read-Through Drugs May allow the translation of MeCP2 even though there is a nonsense or stop mutation (mutations that end in X)

Peter Huppke, Timor Baasov (P)

Jeffrey Neul, Carolyn Schanen, Andrew Napper (P)

Attacks the underlying cause of Rett so has the potential to profoundly impact symptoms

Should not result in too much MECP2 so dosage should not be an issue

Drug may reduce severity but does not eliminate mutation

Drug must be brain penetrant and target a large number of cells

Will only work for nonsense mutations (about 1/3 of all MECP2 mutations)

To date, efficacy of this approach in other diseases has been relatively poor

Development Phase Legend:  Discovery (D) Preclinical (P) Phase 1 (P1) Phase 2 (P2)

Growth Factors and approaches to boost brain neurotrophic factors

Approach How it Works Investigators Advantages Potential Limitations
IGF1 Growth factor signaling

Mriganka Sur (P)

Giorgio Pini (P1)

Walter Kaufmann (P1)

Walter Kaufmann (P2)

Published Phase 1 results show drug to be well tolerated

IGF1 activates signaling pathways that may provide therapeutic benefit

Approved drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Published Phase 1 results showed modest and inconsistent improvements

If approved for Rett will likely only be used for children pre-puberty

 

Injection

Copaxone Boosts brain-derived neurotrophic factor (BDNF)

Andrew Pieper (P)

Ruth Arnon (P)
Rina Aharoni (P)

Sasha Djukic (P2)

Bruria Ben Zeev (P2)

Approved drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

No published behavioral studies in Rett animal models

Injection

Fingolimod Boosts BDNF

Yves Alain Barde (P)

Peter Weber (P1) (P2)

Approved drug – but not in children

Brain penetrant oral drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

High doses of drug impact immune system function

No data for use in children

LM22A-4

Compensates for reduced BDNF levels by directly activating BDNF receptor

David Katz
Frank Longo (P)

Highly specific (may correlate with reduced potential for side effects)

Brain penetrant

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

RP103 Boosts BDNF

Laurent Villard (P)

Raptor Pharmaceuticals (P)

Published animal studies show modest improvement in lifespan and motor skills.

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

Development Phase Legend:  Discovery (D) Preclinical (P) Phase 1 (P1) Phase 2 (P2)

Small Molecule drugs that modulate brain receptor activities

Approach How it Works Investigators Advantages Potential Limitations
Low dose Ketamine Transiently blocks NMDA receptors

David Katz (P)

Michela Fagiolini (P)

Dan Sessler/David Katz (P1)

(Clinical trial undergoing IRB approval process)

 

Preliminary data indicate brief exposure to ketamine reverses multiple disease symptoms in Rett mouse models

Lots of current interest in ketamine because of benefits in depression and other neuropsychiatric disorders

Brain penetrant

Approved drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

High doses can cause hallucinations

Long term effect of chronic use not known

Injection

Dextromethorphan Blocks NMDA receptors

Sakku Bai Naidu (P2) 

Approved drug

Brain penetrant

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Results from open label study reported in ClinicalTrials.gov site show no statistically significant effect on primary outcome measure

Weak NMDA blocker

No published animal studies

Study started in 2004 – no publication yet

SNRM (Subunit-selective NMDA Receptor Modulators) Blocks particular subtypes of NMDA receptors

Mnemosyne Pharmaceuticals
Michela Fagiolini (P)

Highly specific (may correlate with reduced potential for side effects)

Brain penetrant

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

Sarizotan Activates serotonin receptor, 5HT1a

John Bissonnette
Julian Paton  (P)

Newron Pharmaceuticals (P2)

Preclinical studies suggest that activating 5-HT1a receptors improves the breathing pattern in mice

Brain penetrant oral drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

NLX-101 Activates serotonin receptor, 5HT1a

John Bissonnette
Julian Paton (P2 being explored)
Neurolixis (P)

Preclinical studies suggest that activating 5-HT1a receptors improves the breathing pattern in mice

Brain penetrant oral drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

Desipramine Increases levels of noradrenaline

Laurent Villard (P)
Gerard Hilaire
Josette Mancini (P2)

 

Animal studies suggest increasing noradrenaline helps to maintain a normal respiratory rhythm in Rett mouse models

Approved drug (for depression)

Brain penetrant oral drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Desipramine can cause cardiac dysrhythmias – FDA has issued a warning related to this

Study started in 2008 – no publication yet

Vigabatrin Increases GABA levels, a neurotransmitter critical for brain function and is reduced in Rett mouse models

Huda Zoghbi (P)

Already FDA approved and used for selected forms of epilepsy (more abroad than USA)

Brain penetrant

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Retinal toxicity prohibits chronic use

Development Phase Legend:  Discovery (D) Preclinical (P) Phase 1 (P1) Phase 2 (P2)

Other Approaches

Approaches How it Works Investigators Advantages Potential Limitations
NNZ-2566 Anti-inflammatory reduces neuronal degeneration following injury

Jeffrey Neul
Alan Percy
Arthur Beisang
Neuren Pharmaceuticals  (P2)

 

 

Brain penetrant oral drug

Unpublished Phase 2 results announced by Neuren show drug to be safe and well tolerated.

Neuren indicates preliminary efficacy signals suggestive of benefit. Further studies will be necessary to ​​definitively establish whether or not the drug confers clinical benefit.​

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

No published animal studies

Not approved drug yet – longer development timeline

No data for use in children

Statins Addresses imbalances in cholesterol synthesis that may contribute to Rett symptoms

Monica Justice (P)

Sasha Djukic (P2)

Cholesterol pathway is well studied

FDA approved and cheap

Many drugs that work on cholesterol pathway, beyond statins, are available for testing.

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Unknown whether only a certain age group will benefit

Unknown to what degree cholesterol pathway is disrupted in Rett

Topoisomerase inhibitors or other drugs that correct long gene expression MeCP2 appears to turn down protein production of physically long genes. In Rett where MeCP2 is not working properly long genes are upregulated. A drug that lowers expression of long genes can therefore rebalance the situation.

Michael Greenberg

Sacha Nelson (P)

Potentially addresses a root cause of neuronal dysfunction in Rett (altered gene expression), instead of just treating symptoms.

Drugs are already available to facilitate pilot studies testing feasibility and efficacy of treatment in mice (toxicity of these drugs are likely an issue that will have to be addressed before use in humans, see limitations).

Drug may not replace every critical function of MeCP2 so impact may be restricted to subset of symptoms

Topoisomerase inhibitors don’t readily cross the blood brain barrier and are chemotherapy drugs and therefore toxic

REV-003 N/A

Unknown (P)

Revive Therapeutics (P)

Brain penetrant oral drug

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Not approved drug yet – longer development timeline

Animal study not published yet.

EPI-743 There is evidence of mitochondrial dysfunction in Rett. EPI-743 is being developed for mitochondrial diseases

Joussef Hayek
Edison Pharmaceuticals (P2)

Brain penetrant oral drug

Phase 2 results show drug to be well-tolerated and increased head circumference.

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Phase 2 results did not improve primary outcome measure of Rett severity scale.

No published animal studies

Not approved drug yet – longer development timeline

Triheptanoin There is evidence of mitochondrial and metabolic dysfunction in Rett. Triheptanoin restores metabolic imbalance and enhances energy production.

Gabriele Ronnett (P)

Safe drug already in development for other disorders.

Preclinical data looks encouraging.

Drug does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Development Phase Legend:  Discovery (D) Preclinical (P) Phase 1 (P1) Phase 2 (P2)

Procedures

Approach How it Works Investigators Advantages Potential Limitations
Deep Brain Stimulation Treatment used for Parkinson’s, OCD, depression, dystonia and other neurological disorders that could be applicable for Rett.

Huda Zoghbi (P)

James Leiter (P)

Qiu Zilong (P)

Approved procedure for many disorders.

Does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Invasive procedure

Bone Marrow Transplants Microglia may be affected in Rett and a transplant may deliver healthy microglia

Jonathan Kipnis (P)

Approved procedure for many disorders.

Does not address underlying cause of disorder so impact may be restricted to subset of symptoms and/or individuals

Reports from several groups did not observe any benefit of transplant in mouse models

Improvement in symptomatic female mice after transplantation has not been shown.

Procedure is painful, risky and expensive

Development Phase Legend:  Discovery (D) Preclinical (P) Phase 1 (P1) Phase 2 (P2)

Download Table of Treatments