Translating innovative research discoveries to a potential therapeutic for Down S

DESCRIPTION (provided by applicant): Goal: The long term goal is determine whether pentylenetetrazole (PTZ), a previously approved drug with over 30 years of human use, can be a safe and efficacious therapy for patients with DS. The specific goal of the proposed program is to conduct the translational work required to submit an IND with FDA to initiate human clinical studies. Significance: DS is the most common form of DID with a US prevalence of over 350,000 people and incidence of about 1 in 700 births. Currently there are no drugs approved to treat the cognitive impairment in DS and address the huge unmet medical need in this population. It was widely believed that as a congenital condition with multiple trisomic genes, DS was too complex to address through drug therapy. Successful demonstration that PTZ is efficacious in human clinical trials could: 7 Lead to great improvements in the quality of life and productivity of patients with DS. 7 Boost interest in other pharmacological approaches to address DSand other DIDs, which may share a common underlying basis for cognitive disability. 7 Define a development and regulatory path in DS and DIDs that should dramatically reduce future development risk and stimulate significant pharmaceutical RandD investment in the field. Hypothesis: Recent research in a mouse model of DS (Ts65Dn) suggests that a restoration of imbalance between NMDA-mediated excitation and GABAA receptor mediated inhibition through administration of PTZ, a GABAA receptor antagonist results in improved memory and learning [1, 2]. It is hypothesized that over-inhibition also occurs in the brains of patients with DS, and that therapeutic intervention with PTZ can also address the cognitive impairment in this population. Phase 1 Specific Aims:Aim 1): Determine safe and efficacious doses for PTZ in Ts65Dn mice with a focus on seizure risk assessment. Aim 2) Successfully synthesize 1kg scale of drug substance for IND-enabling toxicology studies. Aim 3) Complete preclinical studies needed to support a productive pre-IND meeting with FDA. Aim 4) Create clinical trial synopses and propose clinical approval strategy for pre-IND meeting. Aim 5) Submit pre-IND briefing book and conduct pre-IND meeting with FDA Phase 2 Specific Aims: Aim 1) Develop a suitable clinical formulation and manufacture drug product. Aim 2) Complete safety pharmacology and 28 day toxicology to support IND submission. Aim 3) Complete toxicokinetic, pharmacokinetic, and metabolism studies. Aim 4) Write clinical protocol for firsthuman clinical trial. Aim 5) Prepare and file IND with FDA to allow initiation of clinical trials. Aim 6) Complete 6 and 9 month rat and dog toxicology studies to support Ph 2 trials. 1 PUBLIC HEALTH RELEVANCE: We will be assessing pentylenetetrazole as a potential therapeutic to address the cognitive impairment in patients with Down Syndrome, a congenital condition that affects over 350,000 people in the US, and over 2 million worldwide. Currently there are no drugs approved to treat the cognitive impairment in DS so a safe and efficacious therapeutic would have a major positive impact on the quality of life and productivity of patients with DS. 1 Disclaimer: Please note that the following critiques were prepared by the reviewers prior to theStudy Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.